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1
Orlandi, Elisa, Elisa De Tomi, Rachele Campagnari, Francesca Belpinati, Monica Rodolfo, Elisabetta Vergani, Giovanni Malerba, Macarena Gomez-Lira, Marta Menegazzi, and Maria Romanelli. "Human Melanoma Cells Differentially Express RNASEL/RNase-L and miR-146a-5p under Sex Hormonal Stimulation." Current Issues in Molecular Biology 44, no. 10 (October 11, 2022): 4790–802. http://dx.doi.org/10.3390/cimb44100326.
Повний текст джерелаАнотація:
Polymorphisms in the ribonuclease L (RNASEL) coding gene and hsa-miR-146a-5p (miR-146a) have been associated with melanoma in a sex-specific manner. We hypothesized that RNASEL and miR-146a expression could be influenced by sex hormones playing a role in the female advantages observed in melanoma incidence and survival. Thus, we explored the effects of testosterone and 17β-estradiol on RNASEL and miR-146a expression in LM-20 and A375 melanoma cell lines. Direct targeting of miR-146a to the 3’ untranslated region (3′UTR) of RNASEL was examined using a luciferase reporter system. Our results indicate that RNASEL is a direct target of miR-146a in both melanoma cell lines. Trough qPCR and western blot analyses, we explored the effect of miR-146a mimic transfection in the presence of each hormone either on RNASEL mRNA level or on protein expression of RNase-L, the enzyme codified by RNASEL gene. In the presence of testosterone or 17β-estradiol, miR-146a overexpression did not influence RNASEL transcript level in LM-20 cell line, but it slightly induced RNASEL mRNA level in A375 cells. Remarkably, miR-146a overexpression was able to repress the protein level of RNase-L in both LM-20 and A375 cells in the presence of each hormone, as well as to elicit high expression levels of the activated form of the extracellular signal-regulated kinases (ERK)1/2, hence confirming the pro-tumorigenic role of miR-146a overexpression in melanoma. Thereafter, we assessed if the administration of each hormone could affect the endogenous expression of RNASEL and miR-146a genes in LM-20 and A375 cell lines. Testosterone exerted no significant effect on RNASEL gene expression in both cell lines, while 17β-estradiol enhanced RNASEL transcript level at least in LM-20 melanoma cells. Conversely, miR-146a transcript augmented only in the presence of testosterone in either melanoma cell line. Importantly, each hormone acted quite the opposite regarding the RNase-L protein expression, i.e., testosterone significantly decreased RNase-L expression, whereas 17β-estradiol increased it. Overall, the data show that, in melanoma cells treated with 17β-estradiol, RNase-L expression increased likely by transcriptional induction of its gene. Testosterone, instead, decreased RNase-L expression in melanoma cell lines with a post-transcriptional mechanism in which miR-146a could play a role. In conclusion, the pro-tumor activity of androgen hormone in melanoma cells could be exacerbated by both miR-146a increase and RNase-L downregulation. These events may contribute to the worse outcome in male melanoma patients.
2
Maia, Cláudio Jorge, Sandra Moreira Rocha, Sílvia Socorro, Fernando Schmitt, and Cecília Reis Santos. "Oligoadenylate synthetase 1 (OAS1) expression in human breast and prostate cancer cases, and its regulation by sex steroid hormones." Advances in Modern Oncology Research 2, no. 2 (June 16, 2016): 97. http://dx.doi.org/10.18282/amor.v2.i1.70.
Повний текст джерелаАнотація:
<p>Oligoadenylate synthetase 1 (OAS1) is an interferon-induced protein characterised by its capacity to catalyse the synthesis of 2ʹ-5ʹ-linked oligomers of adenosine from adenosine triphosphate (2-5A). The 2-5A binds to a latent Ribonuclease L (RNase L), which subsequently dimerises into its active form and may play an important role in the control of cell growth, differentiation and apoptosis. Previously, our research group identified <em>OAS1</em> as a differentially-expressed gene in breast and prostate cancer cell lines when compared to normal cells. This study evaluates: i) the expression of <em>OAS1</em> in human breast and prostate cancer specimens; and ii) the effect of sex steroid hormones in regulating the expression of <em>OAS1</em> in breast (MCF-7) and prostate (LNCaP) cancer cell lines. The obtained results showed that <em>OAS1</em> expression was down-regulated in human infiltrative ductal carcinoma of breast, adenocarcinoma of prostate, and benign prostate hyperplasia, both at mRNA and protein level. In addition, <em>OAS1</em> expression was negatively correlated with the progression of breast and prostate cancer. With regards to the regulation of <em>OAS1</em> gene, it was demonstrated that 17β-estradiol (E<sub>2</sub>) down-regulates <em>OAS1</em> gene in MCF-7 cell lines, an effect that seems to be dependent on the activation of oestrogen receptor (ER). On the other hand, 5α‑dihydrotestosterone (DHT) treatment showed no effect on the expression of OAS1 in LNCaP cell lines. The lower levels of OAS1 in breast and prostate cancer cases indicated that the OAS1/RNaseL apoptotic pathway may be compromised in breast and prostate tumours. Moreover, the present findings suggested that this effect may be enhanced by oestrogen in ER-positive breast cancers.</p>
3
Li, Xiao-Ling, John A. Blackford, and Bret A. Hassel. "RNase L Mediates the Antiviral Effect of Interferon through a Selective Reduction in Viral RNA during Encephalomyocarditis Virus Infection." Journal of Virology 72, no. 4 (April 1, 1998): 2752–59. http://dx.doi.org/10.1128/jvi.72.4.2752-2759.1998.
Повний текст джерелаАнотація:
ABSTRACT The 2′,5′-oligoadenylate (2-5A) system is an RNA degradation pathway which plays an important role in the antipicornavirus effects of interferon (IFN). RNase L, the terminal component of the 2-5A system, is thought to mediate this antiviral activity through the degradation of viral RNA; however, the capacity of RNase L to selectively target viral RNA has not been carefully examined in intact cells. Therefore, the mechanism of RNase L-mediated antiviral activity was investigated following encephalomyocarditis virus (EMCV) infection of cell lines in which expression of transfected RNase L was induced or endogenous RNase L activity was inhibited. RNase L induction markedly enhanced the anti-EMCV activity of IFN via a reduction in EMCV RNA. Inhibition of endogenous RNase L activity inhibited this reduction in viral RNA. RNase L had no effect on IFN-mediated protection from vesicular stomatitis virus. RNase L induction reduced the rate of EMCV RNA synthesis, suggesting that RNase L may target viral RNAs involved in replication early in the virus life cycle. The RNase L-mediated reduction in viral RNA occurred in the absence of detectable effects on specific cellular mRNAs and without any global alteration in the cellular RNA profile. Extensive rRNA cleavage, indicative of high levels of 2-5A, was not observed in RNase L-induced, EMCV-infected cells; however, transfection of 2-5A into cells resulted in widespread degradation of cellular RNAs. These findings provide the first demonstration of the selective capacity of RNase L in intact cells and link this selective activity to cellular levels of 2-5A.
4
Scherbik, Svetlana V., Jayashree M. Paranjape, Bronislava M. Stockman, Robert H. Silverman, and Margo A. Brinton. "RNase L Plays a Role in the Antiviral Response to West Nile Virus." Journal of Virology 80, no. 6 (March 15, 2006): 2987–99. http://dx.doi.org/10.1128/jvi.80.6.2987-2999.2006.
Повний текст джерелаАнотація:
ABSTRACT Alleles at the Flv locus determine disease outcome after a flavivirus infection in mice. Although comparable numbers of congenic resistant and susceptible mouse embryo fibroblasts (MEFs) are infected by the flavivirus West Nile virus (WNV), resistant MEFs produce ∼100- to 150-fold lower titers than susceptible ones and flavivirus titers in the brains of resistant and susceptible animals can differ by >10,000-fold. The Flv locus was previously identified as the 2′-5′ oligoadenylate synthetase 1b (Oas1b) gene. Oas gene expression is up-regulated by interferon (IFN), and after activation by double-stranded RNA, some mouse synthetases produce 2-5A, which activates latent RNase L to degrade viral and cellular RNAs. To determine whether the lower levels of intracellular flavivirus genomic RNA from resistant mice detected in cells at all times after infection were mediated by RNase L, RNase L activity levels in congenic resistant and susceptible cells were compared. Similar moderate levels of RNase L activation by transfected 2-5A were observed in both types of uninfected cells. After WNV infection, the mRNAs of IFN-β and three Oas genes were up-regulated to similar levels in both types of cells. However, significant levels of RNase L activity were not detected until 72 h after WNV infection and the patterns of viral RNA cleavage products generated were similar in both types of cells. When RNase L activity was down-regulated in resistant cells via stable expression of a dominant negative RNase L mutant, ∼5- to 10-times-higher yields of WNV were produced. Similarly, about ∼5- to 10-times-higher virus yields were produced by susceptible C57BL/6 RNase L−/− cells compared to RNase L+/+ cells that were either left untreated or pretreated with IFN and/or poly(I) · poly(C). The data indicate that WNV genomic RNA is susceptible to RNase L cleavage and that RNase L plays a role in the cellular antiviral response to flaviviruses. The results suggest that RNase L activation is not a major component of the Oas1b-mediated flavivirus resistance phenotype.
5
Birdwell, L. Dillon, Zachary B. Zalinger, Yize Li, Patrick W. Wright, Ruth Elliott, Kristine M. Rose, Robert H. Silverman, and Susan R. Weiss. "Activation of RNase L by Murine Coronavirus in Myeloid Cells Is Dependent on BasalOasGene Expression and Independent of Virus-Induced Interferon." Journal of Virology 90, no. 6 (January 6, 2016): 3160–72. http://dx.doi.org/10.1128/jvi.03036-15.
Повний текст джерелаАнотація:
ABSTRACTThe oligoadenylate synthetase (OAS)-RNase L pathway is a potent interferon (IFN)-induced antiviral activity. Upon sensing double-stranded RNA, OAS produces 2′,5′-oligoadenylates (2-5A), which activate RNase L. Murine coronavirus (mouse hepatitis virus [MHV]) nonstructural protein 2 (ns2) is a 2′,5′-phosphodiesterase (PDE) that cleaves 2-5A, thereby antagonizing RNase L activation. PDE activity is required for robust replication in myeloid cells, as a mutant of MHV (ns2H126R) encoding an inactive PDE fails to antagonize RNase L activation and replicates poorly in bone marrow-derived macrophages (BMM), while ns2H126Rreplicates to high titer in several types of nonmyeloid cells, as well as in IFN receptor-deficient (Ifnar1−/−) BMM. We reported previously that myeloid cells express significantly higher basal levels of OAS transcripts than nonmyeloid cells. Here, we investigated the contributions ofOasgene expression, basal IFN signaling, and virus-induced IFN to RNase L activation. Infection with ns2H126Ractivated RNase L inIfih1−/−BMM to a similar extent as in wild-type (WT) BMM, despite the lack of IFN induction in the absence of MDA5 expression. However, ns2H126Rfailed to induce RNase L activation in BMM treated with IFNAR1-blocking antibody, as well as inIfnar1−/−BMM, both expressing low basal levels ofOasgenes. Thus, activation of RNase L does not require virus-induced IFN but rather correlates with adequate levels of basalOasgene expression, maintained by basal IFN signaling. Finally, overexpression of RNase L is not sufficient to compensate for inadequate basal OAS levels.IMPORTANCEThe oligoadenylate synthetase (OAS)-RNase L pathway is a potent antiviral activity. Activation of RNase L during murine coronavirus (mouse hepatitis virus [MHV]) infection of myeloid cells correlates with high basalOasgene expression and is independent of virus-induced interferon secretion. Thus, our data suggest that cells with high basalOasgene expression levels can activate RNase L and thereby inhibit virus replication early in infection upon exposure to viral double-stranded RNA (dsRNA) before the induction of interferon and prior to transcription of interferon-stimulated antiviral genes. These findings challenge the notion that activation of the OAS-RNase L pathway requires virus to induce type I IFN, which in turn upregulates OAS gene expression, as well as to provide dsRNA to activate OAS. Our data further suggest that myeloid cells may serve as sentinels to restrict viral replication, thus protecting other cell types from infection.
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Martinand, Camille, Céline Montavon, Tamim Salehzada, Michelle Silhol, Bernard Lebleu, and Catherine Bisbal. "RNase L Inhibitor Is Induced during Human Immunodeficiency Virus Type 1 Infection and Down Regulates the 2-5A/RNase L Pathway in Human T Cells." Journal of Virology 73, no. 1 (January 1, 1999): 290–96. http://dx.doi.org/10.1128/jvi.73.1.290-296.1999.
Повний текст джерелаАнотація:
ABSTRACT The interferon-regulated 2-5A/RNase L pathway plays a major role in the antiviral and antiproliferative activities of these cytokines. Several viruses, however, have evolved strategies to escape the antiviral activity of the 2-5A/RNase L pathway. In this context, we have cloned a cDNA coding for the RNase L inhibitor (RLI), a protein that specifically inhibits RNase L and whose regulated expression in picornavirus-infected cells down regulates the activity of the 2-5A/RNase L pathway. We show here that RLI increases during the course of human immunodeficiency virus type 1 (HIV-1) infection, which may be related to the downregulation of RNase L activity that has been described to occur in HIV-infected cells. In order to establish a possible causal relationship between these observations, we have stably transfected H9 cells with RLI sense or antisense cDNA-expressing vectors. The overexpression of RLI causes a decrease in RNase L activity and a twofold enhancement of HIV production. This increase in HIV replication correlates with an increase in HIV RNA and proteins. In contrast, reduction of RLI levels in RLI antisense cDNA-expressing clones reverses the inhibition of RNase L activity associated with HIV multiplication and leads to a threefold decrease in the viral load. This anti-HIV activity correlated with a decrease in HIV RNA and proteins. These findings demonstrate that the level of RLI, via its modulation of RNase L activity, can severely impair HIV replication and suggest the involvement of RLI in the inhibition of the 2-5A/RNase L system observed during HIV infection.
7
Good-Avila, S. V., D. Majumder, H. Amos, and A. G. Stephenson. "Characterization of self-incompatibility in Campanula rapunculoides (Campanulaceae) through genetic analyses and microscopy." Botany 86, no. 1 (January 2008): 1–13. http://dx.doi.org/10.1139/b07-100.
Повний текст джерелаАнотація:
In this paper, we seek to identify the genetic basis of self-incompatibility (SI) in Campanula rapunculoides L. through diallel analysis of full siblings; to characterize the growth of pollen tubes in vivo after incompatible and compatible pollination; and to determine whether the SI system is based on pistil S-RNases. Pollinations were performed among individuals from five diallel crosses and scored for both fruit set and pollen-tube growth to determine the genetic basis of SI. On a subset of these individuals with known cross-(in)compatibility relationships, additional crosses were performed and pistils collected 1, 3, 6, 12, and 24 h after pollination to assess both the percentage of pollen grains that had germinated on the stigma, and the number of pollen tubes that had grown 20%, 40% 60%, 80%, and 100% of the distance down the pistil over five time intervals. Finally, total pistillate proteins were extracted and subjected to isoelectric focusing and RNase activity staining to find evidence of a highly basic S-RNases associated with SI in the Solanaceae. We found evidence that the SI system was based on the haplotype of the male gametophyte, and was not sporophytic. Protein analyses showed that SI was not based on a pistillate S-RNase. The existence of modifiers of SI and possible polyploidy at the S-locus complicated the expression of SI in this species, and single-gene inheritance could not be determined. This represents the first published characterization of incompatibility in the family Campanulaceae.
8
Maitra, Ratan K., and Robert H. Silverman. "Regulation of Human Immunodeficiency Virus Replication by 2′,5′-Oligoadenylate-Dependent RNase L." Journal of Virology 72, no. 2 (February 1, 1998): 1146–52. http://dx.doi.org/10.1128/jvi.72.2.1146-1152.1998.
Повний текст джерелаАнотація:
ABSTRACT Activation of RNase L by 2′,5′-linked oligoadenylates (2-5A) is one of the antiviral pathways of interferon action. To determine the involvement of the 2-5A system in the control of human immunodeficiency virus type 1 (HIV-1) replication, a segment of the HIV-1nef gene was replaced with human RNase L cDNA. HIV-1 provirus containing sense orientation RNase L cDNA caused increased expression of RNase L and 500- to 1,000-fold inhibition of virus replication in Jurkat cells for a period of about 2 weeks. Subsequently, a partial deletion of the RNase L cDNA which coincided with increases in virus production occurred. The anti-HIV activity of RNase L correlated with decreases in HIV-1 RNA and with an acceleration in cell death accompanied by DNA fragmentation. Replication of HIV-1 encoding RNase L was also transiently suppressed in peripheral blood lymphocytes (PBL). In contrast, recombinant HIV containing reverse orientation RNase L cDNA caused decreased levels of RNase L, increases in HIV yields, and reductions in the anti-HIV effect of alpha interferon in PBL and in Jurkat cells. To obtain constitutive and continuous expression of RNase L cDNA, Jurkat cells were cotransfected with HIV-1 proviral DNA and with plasmid containing a cytomegalovirus promoter driving expression of RNase L cDNA. The RNase L plasmid suppressed HIV-1 replication by eightfold, while an antisense RNase L construct enhanced virus production by twofold. These findings demonstrate that RNase L can severely impair HIV replication and suggest involvement of the 2-5A system in the anti-HIV effect of alpha interferon.
9
Wei, Ruhan, Guanmin Chen, Naseh Algehainy, Chun Zeng, Chunfang Liu, Hongli Liu, Wendy Liu, Dennis Stacey, and Aimin Zhou. "RNase L Is Involved in Liposaccharide-Induced Lung Inflammation." Viruses 12, no. 1 (January 7, 2020): 73. http://dx.doi.org/10.3390/v12010073.
Повний текст джерелаАнотація:
RNase L mediates interferon (IFN) function during viral infection and cell proliferation. Furthermore, the role of RNase L in the regulation of gene expression, cell apoptosis, autophagy, and innate immunity has been well established in the last decade. Tissue distribution reveals that RNase L is highly expressed in the lung and other organs. However, the physiological roles of RNase L in the lung are largely unknown. In this study, we found that polysaccharide (LPS)-induced acute lung injury (ALI) was remarkably intensified in mice deficient in RNase L compared to wild type mice under the same condition. Furthermore, we found that RNase L mediated the TLR4 signaling pathway, and regulated the expression of various pro- and anti-inflammatory genes in the lung tissue and blood. Most importantly, RNase L function in macrophages during LPS stimulation may be independent of the 2-5A system. These findings demonstrate a novel role of RNase L in the immune response via an atypical molecular mechanism.
10
Zhang, Ao, Beihua Dong, Aurélien J. Doucet, John B. Moldovan, John V. Moran, and Robert H. Silverman. "RNase L restricts the mobility of engineered retrotransposons in cultured human cells." Nucleic Acids Research 42, no. 6 (December 25, 2013): 3803–20. http://dx.doi.org/10.1093/nar/gkt1308.
Повний текст джерелаАнотація:
Abstract Retrotransposons are mobile genetic elements, and their mobility can lead to genomic instability. Retrotransposon insertions are associated with a diverse range of sporadic diseases, including cancer. Thus, it is not a surprise that multiple host defense mechanisms suppress retrotransposition. The 2′,5′-oligoadenylate (2-5A) synthetase (OAS)-RNase L system is a mechanism for restricting viral infections during the interferon antiviral response. Here, we investigated a potential role for the OAS-RNase L system in the restriction of retrotransposons. Expression of wild type (WT) and a constitutively active form of RNase L (NΔ385), but not a catalytically inactive RNase L mutant (R667A), impaired the mobility of engineered human LINE-1 (L1) and mouse intracisternal A-type particle retrotransposons in cultured human cells. Furthermore, WT RNase L, but not an inactive RNase L mutant (R667A), reduced L1 RNA levels and subsequent expression of the L1-encoded proteins (ORF1p and ORF2p). Consistently, confocal immunofluorescent microscopy demonstrated that WT RNase L, but not RNase L R667A, prevented formation of L1 cytoplasmic foci. Finally, siRNA-mediated depletion of endogenous RNase L in a human ovarian cancer cell line (Hey1b) increased the levels of L1 retrotransposition by ∼2-fold. Together, these data suggest that RNase L might function as a suppressor of structurally distinct retrotransposons.
11
Rath, Sneha, Jesse Donovan, Gena Whitney, Alisha Chitrakar, Wei Wang, and Alexei Korennykh. "Human RNase L tunes gene expression by selectively destabilizing the microRNA-regulated transcriptome." Proceedings of the National Academy of Sciences 112, no. 52 (December 14, 2015): 15916–21. http://dx.doi.org/10.1073/pnas.1513034112.
Повний текст джерелаАнотація:
Double-stranded RNA (dsRNA) activates the innate immune system of mammalian cells and triggers intracellular RNA decay by the pseudokinase and endoribonuclease RNase L. RNase L protects from pathogens and regulates cell growth and differentiation by destabilizing largely unknown mammalian RNA targets. We developed an approach for transcriptome-wide profiling of RNase L activity in human cells and identified hundreds of direct RNA targets and nontargets. We show that this RNase L-dependent decay selectively affects transcripts regulated by microRNA (miR)-17/miR-29/miR-200 and other miRs that function as suppressors of mammalian cell adhesion and proliferation. RNase L mimics the effects of these miRs and acts as a suppressor of proliferation and adhesion in mammalian cells. Our data suggest that RNase L-dependent decay serves to establish an antiproliferative state via destabilization of the miR-regulated transcriptome.
12
Zeng, Wenbo, Gia-Phong Vu, Yong Bai, Yuan-Chuan Chen, Phong Trang, Sangwei Lu, Gengfu Xiao, and Fenyong Liu. "RNase P-Associated External Guide Sequence Effectively Reduces the Expression of Human CC-Chemokine Receptor 5 and Inhibits the Infection of Human Immunodeficiency Virus 1." BioMed Research International 2013 (2013): 1–12. http://dx.doi.org/10.1155/2013/509714.
Повний текст джерелаАнотація:
External guide sequences (EGSs) represent a new class of RNA-based gene-targeting agents, consist of a sequence complementary to a target mRNA, and render the target RNA susceptible to degradation by ribonuclease P (RNase P). In this study, EGSs were constructed to target the mRNA encoding human CC-chemokine receptor 5 (CCR5), one of the primary coreceptors for HIV. An EGS RNA, C1, efficiently directed human RNase P to cleave the CCR5 mRNA sequencein vitro. A reduction of about 70% in the expression level of both CCR5 mRNA and protein and an inhibition of more than 50-fold in HIV (R5 strain Ba-L) p24 production were observed in cells that expressed C1. In comparison, a reduction of about 10% in the expression of CCR5 and viral growth was found in cells that either did not express the EGS or produced a “disabled” EGS which carried nucleotide mutations that precluded RNase P recognition. Furthermore, the same C1-expressing cells that were protected from R5 strain Ba-L retained susceptibility to X4 strain IIIB, which uses CXCR4 as the coreceptor instead of CCR5, suggesting that the RNase P-mediated cleavage induced by the EGS is specific for the target CCR5 but not the closely related CXCR4. Our results provide direct evidence that EGS RNAs against CCR5 are effective and specific in blocking HIV infection and growth. These results also demonstrate the feasibility to develop highly effective EGSs for anti-HIV therapy.
13
Li, Yize, Shuvojit Banerjee, Yuyan Wang, Stephen A. Goldstein, Beihua Dong, Christina Gaughan, Robert H. Silverman, and Susan R. Weiss. "Activation of RNase L is dependent on OAS3 expression during infection with diverse human viruses." Proceedings of the National Academy of Sciences 113, no. 8 (February 8, 2016): 2241–46. http://dx.doi.org/10.1073/pnas.1519657113.
Повний текст джерелаАнотація:
The 2′,5′-oligoadenylate (2-5A) synthetase (OAS)–RNase L system is an IFN-induced antiviral pathway. RNase L activity depends on 2-5A, synthesized by OAS. Although all three enzymatically active OAS proteins in humans—OAS1, OAS2, and OAS3—synthesize 2-5A upon binding dsRNA, it is unclear which are responsible for RNase L activation during viral infection. We used clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated protein-9 nuclease (Cas9) technology to engineer human A549-derived cell lines in which each of the OAS genes or RNase L is knocked out. Upon transfection with poly(rI):poly(rC), a synthetic surrogate for viral dsRNA, or infection with each of four viruses from different groups (West Nile virus, Sindbis virus, influenza virus, or vaccinia virus), OAS1-KO and OAS2-KO cells synthesized amounts of 2-5A similar to those synthesized in parental wild-type cells, causing RNase L activation as assessed by rRNA degradation. In contrast, OAS3-KO cells synthesized minimal 2-5A, and rRNA remained intact, similar to infected RNase L-KO cells. All four viruses replicated to higher titers in OAS3-KO or RNase L-KO A549 cells than in parental, OAS1-KO, or OAS2-KO cells, demonstrating the antiviral effects of OAS3. OAS3 displayed a higher affinity for dsRNA in intact cells than either OAS1 or OAS2, consistent with its dominant role in RNase L activation. Finally, the requirement for OAS3 as the major OAS isoform responsible for RNase L activation was not restricted to A549 cells, because OAS3-KO cells derived from two other human cell lines also were deficient in RNase L activation.
14
Han, Jian-Qiu, Hannah L. Townsend, Babal Kant Jha, Jayashree M. Paranjape, Robert H. Silverman, and David J. Barton. "A Phylogenetically Conserved RNA Structure in the Poliovirus Open Reading Frame Inhibits the Antiviral Endoribonuclease RNase L." Journal of Virology 81, no. 11 (March 7, 2007): 5561–72. http://dx.doi.org/10.1128/jvi.01857-06.
Повний текст джерелаАнотація:
ABSTRACT RNase L is an antiviral endoribonuclease that cleaves viral mRNAs after single-stranded UA and UU dinucleotides. Poliovirus (PV) mRNA is surprisingly resistant to cleavage by RNase L due to an RNA structure in the 3CPro open reading frame (ORF). The RNA structure associated with the inhibition of RNase L is phylogenetically conserved in group C enteroviruses, including PV type 1 (PV1), PV2, PV3, coxsackie A virus 11 (CAV11), CAV13, CAV17, CAV20, CAV21, and CAV24. The RNA structure is not present in other human enteroviruses (group A, B, or D enteroviruses). Coxsackievirus B3 mRNA and hepatitis C virus mRNA were fully sensitive to cleavage by RNase L. HeLa cells expressing either wild-type RNase L or a dominant-negative mutant RNase L were used to examine the effects of RNase L on PV replication. PV replication was not inhibited by RNase L activity, but rRNA cleavage characteristic of RNase L activity was detected late during the course of PV infection, after assembly of intracellular virus. Rather than inhibiting PV replication, RNase L activity was associated with larger plaques and better cell-to-cell spread. Mutations in the RNA structure associated with the inhibition of RNase L did not affect the magnitude of PV replication in HeLa cells expressing RNase L, consistent with the absence of observed RNase L activity until after virus assembly. Thus, PV carries an RNA structure in the 3C protease ORF that potently inhibits the endonuclease activity of RNase L, but this RNA structure does not prevent RNase L activity late during the course of infection, as virus assembly nears completion.
15
Gupta, Ankush, and Pramod C. Rath. "Curcumin, a Natural Antioxidant, Acts as a Noncompetitive Inhibitor of Human RNase L in Presence of Its Cofactor 2-5AIn Vitro." BioMed Research International 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/817024.
Повний текст джерелаАнотація:
Ribonuclease L (RNase L) is an antiviral endoribonuclease of the innate immune system, which is induced and activated by viral infections, interferons, and double stranded RNA (dsRNA) in mammalian cells. Although, RNase L is generally protective against viral infections, abnormal RNase L expression and activity have been associated with a number of diseases. Here, we show that curcumin, a natural plant-derived anti-inflammatory active principle, inhibits RNase L activity; hence, it may be exploited for therapeutic interventions in case of pathological situations associated with excess activation of RNase L.
16
Bisbal, C., M. Silhol, H. Laubenthal, T. Kaluza, G. Carnac, L. Milligan, F. Le Roy, and T. Salehzada. "The 2′-5′ Oligoadenylate/RNase L/RNase L Inhibitor Pathway Regulates Both MyoD mRNA Stability and Muscle Cell Differentiation." Molecular and Cellular Biology 20, no. 14 (July 15, 2000): 4959–69. http://dx.doi.org/10.1128/mcb.20.14.4959-4969.2000.
Повний текст джерелаАнотація:
ABSTRACT The 2′-5′ oligoadenylate (2-5A)/RNase L pathway is one of the enzymatic pathways induced by interferon. RNase L is a latent endoribonuclease which is activated by 2-5A and inhibited by a specific protein known as RLI (RNase L inhibitor). This system has an important role in regulating viral infection. Additionally, variations in RNase L activity have been observed during cell growth and differentiation but the significance of the 2-5A/RNase L/RLI pathway in these latter processes is not known. To determine the roles of RNase L and RLI in muscle differentiation, C2 mouse myoblasts were transfected with sense and antisense RLI cDNA constructs. Importantly, the overexpression of RLI in C2 cells was associated with diminished RNase L activity, an increased level of MyoD mRNA, and accelerated kinetics of muscle differentiation. Inversely, transfection of the RLI antisense construct was associated with increased RNase L activity, a diminished level of MyoD mRNA, and delayed differentiation. In agreement with these data, MyoD mRNA levels were also decreased in C2 cells transfected with an inducible RNase L construct. The effect of RNase L activity on MyoD mRNA levels was relatively specific because expression of several other mRNAs was not altered in C2 transfectants. Therefore, RNase L is directly involved in myoblast differentiation, probably through its role in regulating MyoD stability. This is the first identification of a potential mRNA target for RNase L.
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Sánchez-Tacuba, Liliana, Margarito Rojas, Carlos F. Arias, and Susana López. "Rotavirus Controls Activation of the 2′-5′-Oligoadenylate Synthetase/RNase L Pathway Using at Least Two Distinct Mechanisms." Journal of Virology 89, no. 23 (September 23, 2015): 12145–53. http://dx.doi.org/10.1128/jvi.01874-15.
Повний текст джерелаАнотація:
ABSTRACTThe innate immune response is the first line of defense of the host cell against a viral infection. In turn, viruses have evolved a wide variety of strategies to hide from, and to directly antagonize, the host innate immune pathways. One of these pathways is the 2′-5′-oligoadenylate synthetase (OAS)/RNase L pathway. OAS is activated by double-stranded RNA (dsRNA) to produce 2′-5′ oligoadenylates, which are the activators of RNase L; this enzyme degrades viral and cellular RNAs, restricting viral infection. It has been recently found that the carboxy-terminal domain (CTD) of rotavirus VP3 has a 2′-5′-phosphodiesterase (PDE) activity that is able to functionally substitute for the PDE activity of the mouse hepatitis virus ns2 protein. This particular phosphodiesterase cleaves the 2′-5′-phosphodiester bond of the oligoadenylates, antagonizing the OAS/RNase L pathway. However, whether this activity of VP3 is relevant during the replication cycle of rotavirus is not known. Here, we demonstrate that after rotavirus infection the OAS/RNase L complex becomes activated; however, the virus is able to control its activity using at least two distinct mechanisms. A virus-cell interaction that occurs during or before rotavirus endocytosis triggers a signal that prevents the early activation of RNase L, while later on the control is taken by the newly synthesized VP3. Cosilencing the expression of VP3 and RNase L in infected cells yields viral infectious particles at levels similar to those obtained in control infected cells, where no genes were silenced, suggesting that the capping activity of VP3 is not essential for the formation of infectious viral particles.IMPORTANCERotaviruses represent an important cause of severe gastroenteritis in the young of many animal species, including humans. In this work, we have found that the OAS/RNase L pathway is activated during rotavirus infection, but the virus uses two different strategies to prevent the deleterious effects of this innate immune response of the cell. Early during virus entry, the initial interactions of the viral particle with the cell result in the inhibition of RNase L activity during the first hours of the infection. Later on, once viral proteins are synthesized, the phosphodiesterase activity of VP3 degrades the cellular 2′-5′-oligoadenylates, which are potent activators of RNase L, preventing its activation. This work demonstrates that the OAS/RNase L pathway plays an important role during infection and that the phosphodiesterase activity of VP3 is relevant during the replication cycle of the virus.
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Li, Yize, and Susan R. Weiss. "Antagonism of RNase L Is Required for Murine Coronavirus Replication in Kupffer Cells and Liver Sinusoidal Endothelial Cells but Not in Hepatocytes." Journal of Virology 90, no. 21 (August 24, 2016): 9826–32. http://dx.doi.org/10.1128/jvi.01423-16.
Повний текст джерелаАнотація:
ABSTRACTMouse hepatitis virus strain A59 infection of mice is a useful tool for studying virus-host interaction during hepatitis development. The NS2H126Rmutant is attenuated in liver replication due to loss of phosphodiesterase activity, which the wild-type (WT) virus uses to block the 2′,5′-oligoadenylate synthetase (OAS)-RNase L (RNase L) antiviral pathway. The activation of RNase L by NS2H126Ris cell type dependent and correlates with high basal expression levels of OAS, as found in myeloid cells. We tested the hypothesis that the resident liver macrophages, Kupffer cells (KC), represent the cell type most likely to restrict NS2H126Rand prevent hepatitis. As found previously, A59 and NS2H126Rreplicate similarly in hepatocytes and neither activates RNase L, as assessed by an rRNA degradation assay. In contrast, in KC, A59 exhibited a 100-fold-higher titer than NS2H126Rand NS2H126Rinduced rRNA degradation. Interestingly, in liver sinusoidal endothelial cells (LSEC), the cells that form a barrier between blood and liver parenchymal cells, NS2H126Ractivates RNase L, which limits viral replication. Similar growth kinetics were observed for the two viruses in KC and LSEC from RNase L−/−mice, demonstrating that both use RNase L to limit NS2H126Rreplication. Depletion of KC by gadolinium(III) chloride or of LSEC by cyclophosphamide partially restores liver replication of NS2H126R, leading to hepatitis. Thus, during mouse hepatitis virus (MHV) infection, hepatitis, which damages the parenchyma, is prevented by RNase L activity in both KC and LSEC but not in hepatocytes. This may be explained by the undetectable levels of RNase L as well as by the OASs expressed in hepatocytes.IMPORTANCEMouse hepatitis virus infection of mice provides a useful tool for studying virus-host interactions during hepatitis development. The NS2H126Rmutant is attenuated in liver replication due to loss of phosphodiesterase activity, by which the wild-type virus blocks the potent OAS-RNase L antiviral pathway. RNase L activation by NS2H126Ris cell type dependent and correlates with high basal expression levels of OAS, as found in myeloid cells. We showed that the hepatocytes that comprise the liver parenchyma do not activate RNase L when infected with NS2H126Ror restrict replication. However, both Kupffer cells (KC) (i.e., the liver-resident macrophages) and the liver sinusoidal endothelial cells (LSEC) which line the sinusoids activate RNase L in response to NS2H126R. These data suggest that KC and LSEC prevent viral spread into the parenchyma, preventing hepatitis. Furthermore, hepatocytes express undetectable levels of OASs and RNase L, which likely explains the lack of RNase L activation during NS2H126Rinfection.
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Manivannan, Praveen, Vidita Reddy, Sushovita Mukherjee, Kirsten Neytania Clark, and Krishnamurthy Malathi. "RNase L Induces Expression of A Novel Serine/Threonine Protein Kinase, DRAK1, to Promote Apoptosis." International Journal of Molecular Sciences 20, no. 14 (July 19, 2019): 3535. http://dx.doi.org/10.3390/ijms20143535.
Повний текст джерелаАнотація:
Apoptosis of virus-infected cells is an effective antiviral mechanism in addition to interferon induction to establish antiviral state to restrict virus spread. The interferon-inducible 2′–5′ oligoadenylate synthetase/RNase L pathway results in activation of RNase L in response to double stranded RNA and cleaves diverse RNA substrates to amplify interferon induction and promote apoptosis. Here we show that RNase L induces expression of Death-associated protein kinase-Related Apoptosis-inducing protein Kinase 1 (DRAK1), a member of the death-associated protein kinase family and interferon-signaling pathway is required for induction. Overexpression of DRAK1 triggers apoptosis in the absence of RNase L activation by activating c-Jun N-terminal kinase (JNK), translocation of BCL2 Associated X (Bax) to the mitochondria accompanied by cytochrome C release and loss of mitochondrial membrane potential promoting cleavage of caspase 3 and Poly(ADP-Ribose) Polymerase 1 (PARP). Inhibitors of JNK and caspase 3 promote survival of DRAK1 overexpressing cells demonstrating an important role of JNK signaling pathway in DRAK1-mediated apoptosis. DRAK1 mutant proteins that lack kinase activity or nuclear localization fail to induce apoptosis highlighting the importance of cellular localization and kinase function in promoting cell death. Our studies identify DRAK1 as a mediator of RNase L-induced apoptosis.
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Weiss, Susan R. "Activation and Antagonism of the OAS–RNase L Pathway." Proceedings 50, no. 1 (June 4, 2020): 14. http://dx.doi.org/10.3390/proceedings2020050014.
Повний текст джерелаАнотація:
The oligoadenylate synthetase–ribonuclease L (OAS–RNase L) system is a potent antiviral pathway that severely limits the pathogenesis of many viruses. Upon sensing dsRNA, OASs produce 2′,5′-oligoadenylates (2-5A) that activate RNase L to cleave both host and viral single-stranded RNA, thereby limiting protein production, virus replication and spread, leading to apoptotic cell death. Endogenous host dsRNA, which accumulates in the absence of adenosine deaminase acting on RNA (ADAR)1, can also activate RNase L and lead to apoptotic cell death. RNase L activation and antiviral activity during infections with several types of viruses in human and bat cells is dependent on OAS3 but independent of virus-induced interferon (IFN) and, thus, RNase L can be activated even in the presence of IFN antagonists. Differently from other human viruses examined, Zika virus is resistant to the antiviral activity of RNase L and instead utilizes RNase L to enhance its replication factories to produce more infectious virus. Some betacoronaviruses antagonize RNase L activation by expressing 2′,5′-phosphodiesterases (PDEs) that cleave 2-5A and thereby antagonize activation of RNase L. The best characterized of these PDEs is the murine coronavirus (MHV) NS2 accessory protein. Enzymatically active NS2 is required for replication in myeloid cells and in the liver. Interestingly, while wild type mice clear MHV from the liver by 7–10 days post-infection, RNase L knockout mice fail to effectively clear MHV, probably due to diminished apoptotic death of infected cells. We suggest that RNase L antiviral activity stems from direct cleavage of viral genomes and cessation of protein synthesis as well as through promoting death of infected cells, limiting the spread of virus. Importantly, OASs are pattern recognition receptors and the OAS–RNase L pathway is a primary innate response pathway to viruses, capable of early response, coming into play before IFN is induced or when the virus shuts down IFN signaling.
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Banerjee, Shuvojit, Elona Gusho, Christina Gaughan, Beihua Dong, Xiaorong Gu, Elise Holvey-Bates, Manisha Talukdar, et al. "OAS-RNase L innate immune pathway mediates the cytotoxicity of a DNA-demethylating drug." Proceedings of the National Academy of Sciences 116, no. 11 (February 27, 2019): 5071–76. http://dx.doi.org/10.1073/pnas.1815071116.
Повний текст джерелаАнотація:
Drugs that reverse epigenetic silencing, such as the DNA methyltransferase inhibitor (DNMTi) 5-azacytidine (AZA), have profound effects on transcription and tumor cell survival. AZA is an approved drug for myelodysplastic syndromes and acute myeloid leukemia, and is under investigation for different solid malignant tumors. AZA treatment generates self, double-stranded RNA (dsRNA), transcribed from hypomethylated repetitive elements. Self dsRNA accumulation in DNMTi-treated cells leads to type I IFN production and IFN-stimulated gene expression. Here we report that cell death in response to AZA treatment occurs through the 2′,5′-oligoadenylate synthetase (OAS)-RNase L pathway. OASs are IFN-induced enzymes that synthesize the RNase L activator 2-5A in response to dsRNA. Cells deficient in RNase L or OAS1 to 3 are highly resistant to AZA, as are wild-type cells treated with a small-molecule inhibitor of RNase L. A small-molecule inhibitor of c-Jun NH2-terminal kinases (JNKs) also antagonizes RNase L-dependent cell death in response to AZA, consistent with a role for JNK in RNase L-induced apoptosis. In contrast, the rates of AZA-induced and RNase L-dependent cell death were increased by transfection of 2-5A, by deficiencies in ADAR1 (which edits and destabilizes dsRNA), PDE12 or AKAP7 (which degrade 2-5A), or by ionizing radiation (which induces IFN-dependent signaling). Finally, OAS1 expression correlates with AZA sensitivity in the NCI-60 set of tumor cell lines, suggesting that the level of OAS1 can be a biomarker for predicting AZA sensitivity of tumor cells. These studies may eventually lead to pharmacologic strategies for regulating the antitumor activity and toxicity of AZA and related drugs.
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Burke, James M., Nina Ripin, Max B. Ferretti, Laura A. St Clair, Emma R. Worden-Sapper, Fernando Salgado, Sara L. Sawyer, Rushika Perera, Kristen W. Lynch, and Roy Parker. "RNase L activation in the cytoplasm induces aberrant processing of mRNAs in the nucleus." PLOS Pathogens 18, no. 11 (November 1, 2022): e1010930. http://dx.doi.org/10.1371/journal.ppat.1010930.
Повний текст джерелаАнотація:
The antiviral endoribonuclease, RNase L, is activated by the mammalian innate immune response to destroy host and viral RNA to ultimately reduce viral gene expression. Herein, we show that RNase L and RNase L-mediated mRNA decay are primarily localized to the cytoplasm. Consequently, RNA-binding proteins (RBPs) translocate from the cytoplasm to the nucleus upon RNase L activation due to the presence of intact nuclear RNA. The re-localization of RBPs to the nucleus coincides with global alterations to RNA processing in the nucleus. While affecting many host mRNAs, these alterations are pronounced in mRNAs encoding type I and type III interferons and correlate with their retention in the nucleus and reduction in interferon protein production. Similar RNA processing defects also occur during infection with either dengue virus or SARS-CoV-2 when RNase L is activated. These findings reveal that the distribution of RBPs between the nucleus and cytosol is dictated by the availability of RNA in each compartment. Thus, viral infections that trigger RNase L-mediated cytoplasmic RNA in the cytoplasm also alter RNA processing in the nucleus, resulting in an ingenious multi-step immune block to protein biogenesis.
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Zeng, Chun, Xin Yi, Danny Zipris, Hongli Liu, Lin Zhang, Qiaoyun Zheng, Krishnamurthy Malathi, Ge Jin, and Aimin Zhou. "RNase L contributes to experimentally induced type 1 diabetes onset in mice." Journal of Endocrinology 223, no. 3 (October 6, 2014): 277–87. http://dx.doi.org/10.1530/joe-14-0509.
Повний текст джерелаАнотація:
The cause of type 1 diabetes continues to be a focus of investigation. Studies have revealed that interferon α (IFNα) in pancreatic islets after viral infection or treatment with double-stranded RNA (dsRNA), a mimic of viral infection, is associated with the onset of type 1 diabetes. However, how IFNα contributes to the onset of type 1 diabetes is obscure. In this study, we found that 2-5A-dependent RNase L (RNase L), an IFNα-inducible enzyme that functions in the antiviral and antiproliferative activities of IFN, played an important role in dsRNA-induced onset of type 1 diabetes. Using RNase L-deficient, rat insulin promoter-B7.1 transgenic mice, which are more vulnerable to harmful environmental factors such as viral infection, we demonstrated that deficiency of RNase L in mice resulted in a significant delay of diabetes onset induced by polyinosinic:polycytidylic acid (poly I:C), a type of synthetic dsRNA, and streptozotocin, a drug which can artificially induce type 1-like diabetes in experimental animals. Immunohistochemical staining results indicated that the population of infiltrated CD8+T cells was remarkably reduced in the islets of RNase L-deficient mice, indicating that RNase L may contribute to type 1 diabetes onset through regulating immune responses. Furthermore, RNase L was responsible for the expression of certain proinflammatory genes in the pancreas under induced conditions. Our findings provide new insights into the molecular mechanism underlying β-cell destruction and may indicate novel therapeutic strategies for treatment and prevention of the disease based on the selective regulation and inhibition of RNase L.
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Yan, Bin, Yujun Liu, Yuan-Chuan Chen, and Fenyong Liu. "A RNase P Ribozyme Inhibits Gene Expression and Replication of Hepatitis B Virus in Cultured Cells." Microorganisms 11, no. 3 (March 3, 2023): 654. http://dx.doi.org/10.3390/microorganisms11030654.
Повний текст джерелаАнотація:
Hepatitis B virus (HBV), an international public health concern, is a leading viral cause of liver disease, such as hepatocellular carcinoma. Sequence-specific ribozymes derived from ribonuclease P (RNase P) catalytic RNA are being explored for gene targeting applications. In this study, we engineered an active RNase P ribozyme, M1-S-A, targeting the overlapping region of HBV S mRNA, pre-S/L mRNA, and pregenomic RNA (pgRNA), all deemed essential for viral infection. Ribozyme M1-S-A cleaved the S mRNA sequence efficiently in vitro. We studied the effect of RNase P ribozyme on HBV gene expression and replication using the human hepatocyte HepG2.2.15 culture model that harbors an HBV genome and supports HBV replication. In these cultured cells, the expression of M1-S-A resulted in a reduction of more than 80% in both HBV RNA and protein levels and an inhibition of about 300-fold in the capsid-associated HBV DNA levels when compared to the cells that did not express any ribozymes. In control experiments, cells expressing an inactive control ribozyme displayed little impact on HBV RNA and protein levels, and on capsid-associated viral DNA levels. Our study signifies that RNase P ribozyme can suppress HBV gene expression and replication, implying the promise of RNase P ribozymes for anti-HBV therapy.
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Fernández-Escobar, Mercedes, José Luis Nájera, Sara Baldanta, Dolores Rodriguez, Michael Way, Mariano Esteban, and Susana Guerra. "Suppression of NYVAC Infection in HeLa Cells Requires RNase L but Is Independent of Protein Kinase R Activity." Journal of Virology 90, no. 4 (December 9, 2015): 2135–41. http://dx.doi.org/10.1128/jvi.02576-15.
Повний текст джерелаАнотація:
Protein kinase R (PKR) and RNase L are host cell components that function to contain viral spread after infections. In this study, we analyzed the role of both proteins in the abortive infection of human HeLa cells with the poxvirus strain NYVAC, for which an inhibition of viralA27LandB5Rgene expression is described. Specifically, the translation of these viral genes is independent of PKR activation, but their expression is dependent on the RNase L activity.
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Smith, Jennifer A., Stephen C. Schmechel, Bryan R. G. Williams, Robert H. Silverman, and Leslie A. Schiff. "Involvement of the Interferon-Regulated Antiviral Proteins PKR and RNase L in Reovirus-Induced Shutoff of Cellular Translation." Journal of Virology 79, no. 4 (February 15, 2005): 2240–50. http://dx.doi.org/10.1128/jvi.79.4.2240-2250.2005.
Повний текст джерелаАнотація:
ABSTRACT Cellular translation is inhibited following infection with most strains of reovirus, but the mechanisms responsible for this phenomenon remain to be elucidated. The extent of host shutoff varies in a strain-dependent manner; infection with the majority of strains leads to strong host shutoff, while infection with strain Dearing results in minimal inhibition of cellular translation. A genetic study with reassortant viruses and subsequent biochemical analyses led to the hypothesis that the interferon-induced, double-stranded RNA-activated protein kinase, PKR, is responsible for reovirus-induced host shutoff. To directly determine whether PKR is responsible for reovirus-induced host shutoff, we used a panel of reovirus strains and mouse embryo fibroblasts derived from knockout mice. This approach revealed that PKR contributes to but is not wholly responsible for reovirus-induced host shutoff. Studies with cells lacking RNase L, the endoribonuclease component of the interferon-regulated 2′,5′-oligoadenylate synthetase-RNase L system, demonstrated that RNase L also down-regulates cellular protein synthesis in reovirus-infected cells. In many viral systems, PKR and RNase L have well-characterized antiviral functions. An analysis of reovirus replication in cells lacking these molecules indicated that, while they contributed to host shutoff, neither PKR nor RNase L exerted an antiviral effect on reovirus growth. In fact, some strains of reovirus replicated more efficiently in the presence of PKR and RNase L than in their absence. Data presented in this report illustrate that the inhibition of cellular translation following reovirus infection is complex and involves multiple interferon-regulated gene products. In addition, our results suggest that reovirus has evolved effective mechanisms to avoid the actions of the interferon-stimulated antiviral pathways that include PKR and RNase L and may even benefit from their expression.
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Aubry, Florence, Marie-Geneviève Mattéi, Jean-Philippe Barque, and Francis Galibert. "Chromosomal localization and expression pattern of the RNase L inhibitor gene." FEBS Letters 381, no. 1-2 (February 26, 1996): 135–39. http://dx.doi.org/10.1016/0014-5793(96)00099-3.
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Magg, Thomas, Tsubasa Okano, Lars M. Koenig, Daniel F. R. Boehmer, Samantha L. Schwartz, Kento Inoue, Jennifer Heimall, et al. "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency." Science Immunology 6, no. 60 (June 18, 2021): eabf9564. http://dx.doi.org/10.1126/sciimmunol.abf9564.
Повний текст джерелаАнотація:
Analysis of autoinflammatory and immunodeficiency disorders elucidates human immunity and fosters the development of targeted therapies. Oligoadenylate synthetase 1 is a type I interferon–induced, intracellular double-stranded RNA (dsRNA) sensor that generates 2′-5′-oligoadenylate to activate ribonuclease L (RNase L) as a means of antiviral defense. We identified four de novo heterozygous OAS1 gain-of-function variants in six patients with a polymorphic autoinflammatory immunodeficiency characterized by recurrent fever, dermatitis, inflammatory bowel disease, pulmonary alveolar proteinosis, and hypogammaglobulinemia. To establish causality, we applied genetic, molecular dynamics simulation, biochemical, and cellular functional analyses in heterologous, autologous, and inducible pluripotent stem cell–derived macrophages and/or monocytes and B cells. We found that upon interferon-induced expression, OAS1 variant proteins displayed dsRNA-independent activity, which resulted in RNase L–mediated RNA cleavage, transcriptomic alteration, translational arrest, and dysfunction and apoptosis of monocytes, macrophages, and B cells. RNase L inhibition with curcumin modulated and allogeneic hematopoietic cell transplantation cured the disorder. Together, these data suggest that human OAS1 is a regulator of interferon-induced hyperinflammatory monocyte, macrophage, and B cell pathophysiology.
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Long, Tiha M., Shahista Nisa, Michael S. Donnenberg, and Bret A. Hassel. "Enteropathogenic Escherichia coli Inhibits Type I Interferon- and RNase L-Mediated Host Defense To Disrupt Intestinal Epithelial Cell Barrier Function." Infection and Immunity 82, no. 7 (April 14, 2014): 2802–14. http://dx.doi.org/10.1128/iai.00105-14.
Повний текст джерелаАнотація:
ABSTRACTEnteropathogenicEscherichia coli(EPEC) primarily infects children in developing countries and causes diarrhea that can be deadly. EPEC pathogenesis occurs through type III secretion system (T3SS)-mediated injection of effectors into intestinal epithelial cells (IECs); these effectors alter actin dynamics, modulate the immune response, and disrupt tight junction (TJ) integrity. The resulting compromised barrier function and increased gastrointestinal (GI) permeability may be responsible for the clinical symptoms of infection. Type I interferon (IFN) mediates anti-inflammatory activities and serves essential functions in intestinal immunity and homeostasis; however, its role in the immune response to enteric pathogens, such as EPEC, and its impact on IEC barrier function have not been examined. Here, we report that IFN-β is induced following EPEC infection and regulates IEC TJ proteins to maintain barrier function. The EPEC T3SS effector NleD counteracts this protective activity by inhibiting IFN-β induction and enhancing tumor necrosis factor alpha to promote barrier disruption. The endoribonuclease RNase L is a key mediator of IFN induction and action that promotes TJ protein expression and IEC barrier integrity. EPEC infection inhibits RNase L in a T3SS-dependent manner, providing a mechanism by which EPEC evades IFN-induced antibacterial activities. This work identifies novel roles for IFN-β and RNase L in IEC barrier functions that are targeted by EPEC effectors to escape host defense mechanisms and promote virulence. The IFN-RNase L axis thus represents a potential therapeutic target for enteric infections and GI diseases involving compromised barrier function.
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Ludwig, Holger, Yasemin Suezer, Zoe Waibler, Ulrich Kalinke, Barbara S. Schnierle, and Gerd Sutter. "Double-stranded RNA-binding protein E3 controls translation of viral intermediate RNA, marking an essential step in the life cycle of modified vaccinia virus Ankara." Journal of General Virology 87, no. 5 (May 1, 2006): 1145–55. http://dx.doi.org/10.1099/vir.0.81623-0.
Повний текст джерелаАнотація:
Infection of human cells with modified vaccinia virus Ankara (MVA) activates the typical cascade-like pattern of viral early-, intermediate- and late-gene expression. In contrast, infection of human HeLa cells with MVA deleted of the E3L gene (MVA-ΔE3L) results in high-level synthesis of intermediate RNA, but lacks viral late transcription. The viral E3 protein is thought to bind double-stranded RNA (dsRNA) and to act as an inhibitor of dsRNA-activated 2′-5′-oligoadenylate synthetase (2′-5′OA synthetase)/RNase L and protein kinase (PKR). Here, it is demonstrated that viral intermediate RNA can form RNase A/T1-resistant dsRNA, suggestive of activating both the 2′-5′OA synthetase/RNase L pathway and PKR in various human cell lines. Western blot analysis revealed that failure of late transcription in the absence of E3L function resulted from the deficiency to produce essential viral intermediate proteins, as demonstrated for vaccinia late transcription factor 2 (VLTF 2). Substantial host cell-specific differences were found in the level of activation of either RNase L or PKR. However, both rRNA degradation and phosphorylation of eukaryotic translation initiation factor-2α (eIF2α) inhibited the synthesis of VLTF 2 in human cells. Moreover, intermediate VLTF 2 and late-protein production were restored in MVA-ΔE3L-infected mouse embryonic fibroblasts from Pkr 0/0 mice. Thus, both host-response pathways may be involved, but activity of PKR is sufficient to block the MVA molecular life cycle. These data imply that an essential function of vaccinia virus E3L is to secure translation of intermediate RNA and, thereby, expression of other viral genes.
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Xiang, Ying, David A. Simpson, Jason Spiegel, Aimin Zhou, Robert H. Silverman, and Richard C. Condit. "The Vaccinia Virus A18R DNA Helicase Is a Postreplicative Negative Transcription Elongation Factor." Journal of Virology 72, no. 9 (September 1, 1998): 7012–23. http://dx.doi.org/10.1128/jvi.72.9.7012-7023.1998.
Повний текст джерелаАнотація:
ABSTRACT Loss of vaccinia virus A18R gene function results in an aberrant transcription profile termed promiscuous transcription, defined as transcription within regions of the genome which are normally transcriptionally silent late during infection. Promiscuous transcription results in an increase in the intracellular concentration of double-stranded RNA, which in turn results in activation of the cellular 2-5A pathway and subsequent RNase L-catalyzed degradation of viral and cellular RNAs. One of three hypotheses could account for promiscuous transcription: (i) reactivation of early promoters late during infection, (ii) random transcription initiation, (iii) readthrough transcription from upstream promoters. Transcriptional analysis of several viral genes, presented here, argues strongly against the first two hypotheses. We have tested the readthrough hypothesis by conducting a detailed transcriptional analysis of a region of the vaccinia virus genome which contains three early genes (M1L, M2L, and K1L) positioned directly downstream of the intermediate gene, K2L. The results show that mutation of the A18R gene results in increased readthrough transcription of the M1L gene originating from the K2L intermediate promoter. A18R mutant infection of RNase L knockout mouse fibroblast (KO3) cells does not result in 2-5A pathway activation, yet the virus mutant is defective in late viral gene expression and remains temperature sensitive. These results demonstrate that the A18R gene product is a negative transcription elongation factor for postreplicative viral genes.
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Kocić, Gordana, Jovan Hadzi-Djokić, Andrej Veljković, Stefanos Roumeliotis, Ljubinka Janković-Veličković, and Andrija Šmelcerović. "Template-Independent Poly(A)-Tail Decay and RNASEL as Potential Cellular Biomarkers for Prostate Cancer Development." Cancers 14, no. 9 (April 29, 2022): 2239. http://dx.doi.org/10.3390/cancers14092239.
Повний текст джерелаАнотація:
The post-transcriptional messenger RNA (mRNA) decay and turnover rate of the template-independent poly(A) tail, localized at the 3′-untranslated region (3′UTR) of mRNA, have been documented among subtle mechanisms of uncontrolled cancer tissue growth. The activity of Poly(A) deadenylase and the expression pattern of RNASEL have been examined. A total of 138 prostate tissue specimens from 46 PC patients (cancer specimens, corresponding adjacent surgically healthy tissues, and in their normal counterparts, at least 2 cm from carcinoma) were used. For the stratification prediction of healthy tissue transition into malignant phenotype, the enzyme activity of tumor-adjacent tissue was considered in relation to the presence of microfocal carcinoma. More than a four-times increase in specific enzyme activity (U/L g.prot) was registered in PC on account of both the dissociation of its inhibitor and genome reprogramming. The obtained ROC curve and Youden index showed that Poly(A) deadenylase identified PC with a sensitivity of 93.5% and a specificity of 94.6%. The RNASEL expression profile was raised significantly in PC, but the sensitivity was 40.5% and specificity was 86.9%. A significantly negative correlation between PC and control tissue counterparts with a higher expression pattern in lymphocyte-infiltrated samples were reported. In conclusion, significantly upregulated Poly(A) deadenylase activity may be a checkpoint for the transition of precancerous lesion to malignancy, while RNASEL may predict chronic inflammation.
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Obolenskaya, M. Yu, L. Ya Sazonova, T. B. Gerasimova, S. L. Rybalko, and C. Bisbal. "RNAse L and genome expression during early period of the rat liver regeneration." Biopolymers and Cell 16, no. 5 (September 20, 2000): 380–83. http://dx.doi.org/10.7124/bc.000580.
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Du, Xi-ling, Dong Wang, Xiao-yin Qian, Li-zhi Jiang, Wei Chun, Ke-gui Li, Guo-an Shen, Chang-fa Lin, and Jin-shui Yang. "cDNA Cloning and Expression Analysis of the Rice (Oryza sativaL.) RNase L Inhibitor." DNA Sequence 14, no. 4 (July 2003): 295–301. http://dx.doi.org/10.1080/1085566031000141162.
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Liu, Ruikang, and Bernard Moss. "Opposing Roles of Double-Stranded RNA Effector Pathways and Viral Defense Proteins Revealed with CRISPR-Cas9 Knockout Cell Lines and Vaccinia Virus Mutants." Journal of Virology 90, no. 17 (June 22, 2016): 7864–79. http://dx.doi.org/10.1128/jvi.00869-16.
Повний текст джерелаАнотація:
ABSTRACTVaccinia virus (VACV) decapping enzymes and cellular exoribonuclease Xrn1 catalyze successive steps in mRNA degradation and prevent double-stranded RNA (dsRNA) accumulation, whereas the viral E3 protein can bind dsRNA. We showed that dsRNA and E3 colocalized within cytoplasmic viral factories in cells infected with a decapping enzyme mutant as well as with wild-type VACV and that they coprecipitated with antibody. An E3 deletion mutant induced protein kinase R (PKR) and eukaryotic translation initiation factor alpha (eIF2α) phosphorylation earlier and more strongly than a decapping enzyme mutant even though less dsRNA was made, leading to more profound effects on viral gene expression. Human HAP1 and A549 cells were genetically modified by clustered regularly interspaced short palindromic repeat-Cas9 (CRISPR-Cas9) to determine whether the same pathways restrict E3 and decapping mutants. The E3 mutant replicated in PKR knockout (KO) HAP1 cells in which RNase L is intrinsically inactive but only with a double knockout (DKO) of PKR and RNase L in A549 cells, indicating that both pathways decreased replication equivalently and that no additional dsRNA pathway was crucial. In contrast, replication of the decapping enzyme mutant increased significantly (though less than that of wild-type virus) in DKO A549 cells but not in DKO HAP1 cells where a smaller increase in viral protein synthesis occurred. Xrn1 KO A549 cells were viable but nonpermissive for VACV; however, wild-type and mutant viruses replicated in triple-KO cells in which RNase L and PKR were also inactivated. Since KO of PKR and RNase L was sufficient to enable VACV replication in the absence of E3 or Xrn1, the poor replication of the decapping mutant, particularly in HAP1 DKO, cells indicated additional translational defects.IMPORTANCEViruses have evolved ways of preventing or counteracting the cascade of antiviral responses that double-stranded RNA (dsRNA) triggers in host cells. We showed that the dsRNA produced in excess in cells infected with a vaccinia virus (VACV) decapping enzyme mutant and by wild-type virus colocalized with the viral E3 protein in cytoplasmic viral factories. Novel human cell lines defective in either or both protein kinase R and RNase L dsRNA effector pathways and/or the cellular 5′ exonuclease Xrn1 were prepared by CRISPR-Cas9 gene editing. Inactivation of both pathways was necessary and sufficient to allow full replication of the E3 mutant and reverse the defect cause by inactivation of Xrn1, whereas the decapping enzyme mutant still exhibited defects in gene expression. The study provided new insights into functions of the VACV proteins, and the well-characterized panel of CRISPR-Cas9-modified human cell lines should have broad applicability for studying innate dsRNA pathways.
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Qian, Yisong, Xiuzhen Li, Ruidong Miao, Shufeng Liu, Hong-Bo Xin, Xiaotian Huang, Tony T. Wang, and Mingui Fu. "Selective degradation of plasmid-derived mRNAs by MCPIP1 RNase." Biochemical Journal 476, no. 19 (October 11, 2019): 2927–38. http://dx.doi.org/10.1042/bcj20190646.
Повний текст джерелаАнотація:
Abstract Detection and degradation of foreign nucleic acids is an ancient form of host defense. However, the underlying mechanisms are not completely clear. MCPIP1 is an endoribonuclease and an important regulator in both innate and adaptive immunity by targeting inflammatory mRNA degradation. Here we report that MCPIP1 RNase can also selectively detect and degrade the mRNAs encoded by transfected plasmids. In transient transfection, MCPIP1 expression potently degraded the mRNA from exogenously transfected vectors, which is independent on the vector, genes and cell types used. Conversely, the expression of transfected plasmids in MCPIP1-null cells is significantly higher than that in wild-type cells. Interestingly, overexpression of MCPIP1 or MCPIP1 deficiency does not affect the expression of the exogenous genes incorporated into the host genome in a stable cell line or the global gene expression of host genome. This ability is not associated with PKR/RNase L system, as PKR inhibitors does not block MCPIP1-mediated mRNA degradation of exogenously transfected genes. Lastly, expression of MCPIP1 suppressed replication of Zika virus in infected cells. The study may provide a model for understanding the antiviral mechanisms of MCPIP1, and a putative tool to increase the expression of transfected exogenous genes.
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Luthra, Priya, Dengyun Sun, Robert H. Silverman та Biao He. "Activation of IFN-β expression by a viral mRNA through RNase L and MDA5". Proceedings of the National Academy of Sciences 108, № 5 (18 січня 2011): 2118–23. http://dx.doi.org/10.1073/pnas.1012409108.
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Reuter, Thorsten, Benedikt Weissbrich, Sibylle Schneider-Schaulies, and Jürgen Schneider-Schaulies. "RNA Interference with Measles Virus N, P, and L mRNAs Efficiently Prevents and with Matrix Protein mRNA Enhances Viral Transcription." Journal of Virology 80, no. 12 (June 15, 2006): 5951–57. http://dx.doi.org/10.1128/jvi.02453-05.
Повний текст джерелаАнотація:
ABSTRACT In contrast to studies with genetically modified viruses, RNA interference allows the analysis of virus infections with identical viruses and posttranscriptional ablation of individual gene functions. Using RNase III-generated multiple short interfering RNAs (siRNAs) against the six measles virus genes, we found efficient downregulation of viral gene expression in general with siRNAs against the nucleocapsid (N), phosphoprotein (P), and polymerase (L) mRNAs, the translation products of which form the ribonucleoprotein (RNP) complex. Silencing of the RNP mRNAs was highly efficient in reducing viral messenger and genomic RNAs. siRNAs against the mRNAs for the hemagglutinin (H) and fusion (F) proteins reduced the extent of cell-cell fusion. Interestingly, siRNA-mediated knockdown of the matrix (M) protein not only enhanced cell-cell fusion but also increased the levels of both mRNAs and genomic RNA by a factor of 2 to 2.5 so that the genome-to-mRNA ratio was constant. These findings indicate that M acts as a negative regulator of viral polymerase activity, affecting mRNA transcription and genome replication to the same extent.
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Iordanov, Mihail S., John Wong, John C. Bell та Bruce E. Magun. "Activation of NF-κB by Double-Stranded RNA (dsRNA) in the Absence of Protein Kinase R and RNase L Demonstrates the Existence of Two Separate dsRNA-Triggered Antiviral Programs". Molecular and Cellular Biology 21, № 1 (1 січня 2001): 61–72. http://dx.doi.org/10.1128/mcb.21.1.61-72.2001.
Повний текст джерелаАнотація:
ABSTRACT Double-stranded RNA (dsRNA) of viral origin triggers two programs of the innate immunity in virus-infected cells. One is intended to decrease the rate of host cell protein synthesis and thus to prevent viral replication. This program is mediated by protein kinase R (PKR) and by RNase L and contributes, eventually, to the self-elimination of the infected cell via apoptosis. The second program is responsible for the production of antiviral (type I) interferons and other alarmone cytokines and serves the purpose of preparing naive cells for the viral invasion. This second program requires the survival of the infected cell and depends on the expression of antiapoptotic genes through the activation of the NF-κB transcription factor. The second program therefore relies on ongoing transcription and translation. It has been proposed that PKR plays an essential role in the activation of NF-κB by dsRNA. Here we present evidence that the dsRNA-induced NF-κB activity and the expression of beta interferon and inflammatory cytokines do not require either PKR or RNase L. Our results indicate, therefore, that the two dsRNA-activated programs are separate and can function independently of each other.
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Tesfay, Mulu Z., Jun Yin, Christina L. Gardner, Mikhail V. Khoretonenko, Nadejda L. Korneeva, Robert E. Rhoads, Kate D. Ryman, and William B. Klimstra. "Alpha/Beta Interferon Inhibits Cap-Dependent Translation of Viral but Not Cellular mRNA by a PKR-Independent Mechanism." Journal of Virology 82, no. 6 (December 26, 2007): 2620–30. http://dx.doi.org/10.1128/jvi.01784-07.
Повний текст джерелаАнотація:
ABSTRACT The alpha/beta interferon (IFN-α/β) response is critical for host protection against disseminated replication of many viruses, primarily due to the transcriptional upregulation of genes encoding antiviral proteins. Previously, we determined that infection of mice with Sindbis virus (SB) could be converted from asymptomatic to rapidly fatal by elimination of this response (K. D. Ryman et al., J. Virol. 74:3366-3378, 2000). Probing of the specific antiviral proteins important for IFN-mediated control of virus replication indicated that the double-stranded RNA-dependent protein kinase, PKR, exerted some early antiviral effects prior to IFN-α/β signaling; however, the ability of IFN-α/β to inhibit SB and protect mice from clinical disease was essentially undiminished in the absence of PKR, RNase L, and Mx proteins (K. D. Ryman et al., Viral Immunol. 15:53-76, 2002). One characteristic of the PKR/RNase L/Mx-independent antiviral effect was a blockage of viral protein accumulation early after infection (K. D. Ryman et al., J. Virol. 79:1487-1499, 2005). We show here that IFN-α/β priming induces a PKR-independent activity that inhibits m7G cap-dependent translation at a step after association of cap-binding factors and the small ribosome subunit but before formation of the 80S ribosome. Furthermore, the activity targets mRNAs that enter across the cytoplasmic membrane, but nucleus-transcribed RNAs are relatively unaffected. Therefore, this IFN-α/β-induced antiviral activity represents a mechanism through which IFN-α/β-exposed cells are defended against viruses that enter the cytoplasm, while preserving essential host activities, including the expression of antiviral and stress-responsive genes.
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Luo, Zhao-Qing, and Stephen K. Farrand. "The Agrobacterium tumefaciens rndHomolog Is Required for TraR-Mediated Quorum-Dependent Activation of Ti Plasmid tra Gene Expression." Journal of Bacteriology 183, no. 13 (July 1, 2001): 3919–30. http://dx.doi.org/10.1128/jb.183.13.3919-3930.2001.
Повний текст джерелаАнотація:
ABSTRACT Conjugal transfer of Agrobacterium tumefaciens Ti plasmids is regulated by quorum sensing via TraR and its cognate autoinducer, N-(3-oxo-octanoyl)-l-homoserine lactone. We isolated four Tn5-induced mutants of A. tumefaciens C58 deficient in TraR-mediated activation oftra genes on pTiC58ΔaccR. These mutations also affected the growth of the bacterium but had no detectable influence on the expression of two tester gene systems that are not regulated by quorum sensing. In all four mutants Tn5 was inserted in a chromosomal open reading frame (ORF) coding for a product showing high similarity to RNase D, coded for by rnd ofEscherichia coli, an RNase known to be involved in tRNA processing. The wild-type allele of the rnd homolog cloned from C58 restored the two phenotypes to each mutant. Several ORFs, including a homolog of cya2, surround A. tumefaciens rnd, but none of these genes exerted a detectable effect on the expression of the tra reporter. In the mutant,traR was expressed from the Ti plasmid at a level about twofold lower than that in NT1. The expression of tra, but not the growth rate, was partially restored by increasing the copy number of traR or by disrupting traM, a Ti plasmid gene coding for an antiactivator specific for TraR. The mutation in rnd also slightly reduced expression of two tested vir genes but had no detectable effect on tumor induction by this mutant. Our data suggest that the defect intra gene induction in the mutants results from lowered levels of TraR. In turn, production of sufficient amounts of TraR apparently is sensitive to a cellular function requiring RNase D.
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Angus, Steven P., Timothy Stuhlmiller, Noah Sciaky, Xin Chen, Rashid Naim, Maki Tanioka, Kristalyn K. Gallagher, et al. "TBCRC 036: Window of opportunity clinical trial reveals adaptive kinome reprogramming in single and combination HER2-targeting in breast cancer (BrCa)." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 1027. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.1027.
Повний текст джерелаАнотація:
1027 Background: HER2 targeting is challenging due to heterogeneity in response and resistance. Adaptive kinome reprogramming (AKRP) is a resistance mechanism to kinase-targeted therapy (Rx) in TNBC ( Cancer Discovery2017). We studied AKRP in HER2+ BrCa by comparing transcriptome and kinome profiles before and after Rx with FDA-approved anti-HER2 drugs and combinations: trastuzumab (T), pertuzumab (P), T+P, or T+ lapatinib (T+L). Profiling was by RNA sequencing (RNAseq) and multiplexed inhibitor beads coupled with mass spectrometry (MIB/MS). MIB affinity-purification selectively enriches the functional kinome ( > 250 kinases per sample) for identification/quantification by MS. Methods: Eligible patients (pts) had biopsy then randomization to: T (8 mg/kg iv), P (840 mg iv), T+P (same doses), or T+L (8mg/kg iv x1, 1000 mg po/d) 7 days before breast surgery. RNAseq and MIB/MS on paired pre- and post-Rx samples were analyzed using DESeq2 (comparison of mean difference in log2fold change (post/pre)) and MaxQuant (kinome response profiling) software. Results: Of 23 evaluable pts, we obtained informative paired RNAseq data in 13 (5 T, 3 P, 3 T+P, 2 T+L), and identified distinct expression responses (padj≤0.05) between Rx arms, such as FGFR4 increase in P vs T or T+P. All samples had HER2 enrichment by RNAseq. Kinome response profiling from 11 pts (3 T, 3 P, 4 T+P, 2 T+L) revealed consistent increases in MIB binding (abundance a/o activity) of several tyrosine kinases regardless of Rx, including immune-related kinases SYK, IRAK4, FGR, and FES. Other kinases, such as p90Rsk and GSK3B, exhibited increased binding in response to T and T+P, but not P alone. While not quantifiable in every sample due to detection limits, HER2 inhibition was observed by loss of MIB binding in select post-Rx versus pre-Rx comparisons. Conclusions: HER2 inhibition upregulates and activates specific receptor tyrosine kinases in tumor cells as well as alterations that may reflect changes in the immune compartment. HER2+ BrCa exhibit plasticity, characterized by distinct expression and kinome profile changes within 1 week of initiating Rx, and reprogramming in both immune responses and BrCa cells. Clinical trial information: NCT01875666.
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Van den Bergh, F., and R. L. Sabina. "Characterization of human AMP deaminase 2 (AMPD2) gene expression reveals alternative transcripts encoding variable N-terminal extensions of isoform L." Biochemical Journal 312, no. 2 (December 1, 1995): 401–10. http://dx.doi.org/10.1042/bj3120401.
Повний текст джерелаАнотація:
AMP deaminase (AMPD) is a highly regulated enzymic activity and multiple isoforms of this enzyme are coded for by a multigene family in mammalian species, including man. Isoform L (liver) is the main activity present in adult human liver and is the protein product of the AMPD2 gene, which is widely expressed in non-muscle tissues and cells. A previous report described almost the full-length cDNA sequence and part of the human AMPD2 gene and also presented Northern blot evidence for multiple transcripts in brain. This study was performed to further characterize the AMPD2 gene and its expression in human tissues. AMPD2 genomic and human cerebellum cDNA clones were isolated, sequenced and used as probes in RNase protection analyses which together demonstrated the following: (1) an intervening sequence near the 5′-end of the published AMPD2 cDNA, which affects the predicted N-terminal amino acid sequence of isoform L; (2) alternative transcripts resulting from exon shuffling at, or near, the 5′-end of the AMPD2 gene that exhibit tissue-specific patterns of relative abundance; (3) predicted usage of three different initiation codons to confer variable N-terminal extensions on isoform L polypeptides; and (4) an extension of a 3′ untranslated sequence in some AMPD2 transcripts. In addition, reverse transcriptase PCR and additional RNase protection analyses were used to map the 5′-ends of two mutually-exclusive exon 1 sequences, both of which contain multiple transcription-initiation sites. These results are discussed in relation to predicted isoform L diversity across human tissues and cells.
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Child, Stephanie J., Sohail Jarrahian, Victoria M. Harper, and Adam P. Geballe. "Complementation of Vaccinia Virus Lacking the Double-Stranded RNA-Binding Protein Gene E3L by Human Cytomegalovirus." Journal of Virology 76, no. 10 (May 15, 2002): 4912–18. http://dx.doi.org/10.1128/jvi.76.10.4912-4918.2002.
Повний текст джерелаАнотація:
ABSTRACT The cellular response to viral infection often includes activation of pathways that shut off protein synthesis and thereby inhibit viral replication. In order to enable efficient replication, many viruses carry genes such as the E3L gene of vaccinia virus that counteract these host antiviral pathways. Vaccinia virus from which the E3L gene has been deleted (VVΔE3L) is highly sensitive to interferon and exhibits a restricted host range, replicating very inefficiently in many cell types, including human fibroblast and U373MG cells. To determine whether human cytomegalovirus (CMV) has a mechanism for preventing translational shutoff, we evaluated the ability of CMV to complement the deficiencies in replication and protein synthesis associated with VVΔE3L. CMV, but not UV-inactivated CMV, rescued VVΔE3L late gene expression and replication. Thus, complementation of the VVΔE3L defect appears to depend on de novo CMV gene expression and is not likely a result of CMV binding to the cell receptor or of a virion structural protein. CMV rescued VVΔE3L late gene expression even in the presence of ganciclovir, indicating that CMV late gene expression is not required for complementation of VVΔE3L. The striking decrease in overall translation after infection with VVΔE3L was prevented by prior infection with CMV. Finally, CMV blocked both the induction of eukaryotic initiation factor 2α (eIF2α) phosphorylation and activation of RNase L by VVΔE3L. These results suggest that CMV has one or more immediate-early or early genes that ensure maintenance of a high protein synthetic capacity during infection by preventing activation of the PKR/eIF2α phosphorylation and 2-5A oligoadenylate synthetase/RNase L pathways.
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Gupta, Ankush, and Pramod C. Rath. "Expression of mRNA and protein–protein interaction of the antiviral endoribonuclease RNase L in mouse spleen." International Journal of Biological Macromolecules 69 (August 2014): 307–18. http://dx.doi.org/10.1016/j.ijbiomac.2014.04.042.
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Gupta, Ankush, and Pramod C. Rath. "Expression, purification and characterization of the interferon-inducible, antiviral and tumour-suppressor protein, human RNase L." Journal of Biosciences 37, no. 1 (January 19, 2012): 103–13. http://dx.doi.org/10.1007/s12038-011-9180-4.
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Esposito, Salvatore, Riccardo Aversano, Pasquale Tripodi, and Domenico Carputo. "Whole-Genome Doubling Affects Pre-miRNA Expression in Plants." Plants 10, no. 5 (May 18, 2021): 1004. http://dx.doi.org/10.3390/plants10051004.
Повний текст джерелаАнотація:
Whole-genome doubling (polyploidy) is common in angiosperms. Several studies have indicated that it is often associated with molecular, physiological, and phenotypic changes. Mounting evidence has pointed out that micro-RNAs (miRNAs) may have an important role in whole-genome doubling. However, an integrative approach that compares miRNA expression in polyploids is still lacking. Here, a re-analysis of already published RNAseq datasets was performed to identify microRNAs’ precursors (pre-miRNAs) in diploids (2x) and tetraploids (4x) of five species (Arabidopsis thaliana L., Morus alba L., Brassica rapa L., Isatis indigotica Fort., and Solanum commersonii Dun). We found 3568 pre-miRNAs, three of which (pre-miR414, pre-miR5538, and pre-miR5141) were abundant in all 2x, and were absent/low in their 4x counterparts. They are predicted to target more than one mRNA transcript, many belonging to transcription factors (TFs), DNA repair mechanisms, and related to stress. Sixteen pre-miRNAs were found in common in all 2x and 4x. Among them, pre-miRNA482, pre-miRNA2916, and pre-miRNA167 changed their expression after polyploidization, being induced or repressed in 4x plants. Based on our results, a common ploidy-dependent response was triggered in all species under investigation, which involves DNA repair, ATP-synthesis, terpenoid biosynthesis, and several stress-responsive transcripts. In addition, an ad hoc pre-miRNA expression analysis carried out solely on 2x vs. 4x samples of S. commersonii indicated that ploidy-dependent pre-miRNAs seem to actively regulate the nucleotide metabolism, probably to cope with the increased requirement for DNA building blocks caused by the augmented DNA content. Overall, the results outline the critical role of microRNA-mediated responses following autopolyploidization in plants.
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Da Ros, Letitia, Raed Elferjani, Raju Soolanayakanahally, Sateesh Kagale, Shankar Pahari, Manoj Kulkarni, Jazeem Wahab, and Benoit Bizimungu. "Drought-Induced Regulatory Cascades and Their Effects on the Nutritional Quality of Developing Potato Tubers." Genes 11, no. 8 (July 30, 2020): 864. http://dx.doi.org/10.3390/genes11080864.
Повний текст джерелаАнотація:
Competition for scarce water resources and the continued effects of global warming exacerbate current constraints on potato crop production. While plants’ response to drought in above-ground tissues has been well documented, the regulatory cascades and subsequent nutritive changes in developing tubers have been largely unexplored. Using the commercial Canadian cultivar “Vigor”, plants were subjected to a gradual drought treatment under high tunnels causing a 4 °C increase in the canopy temperature. Tubers were sampled for RNAseq and metabolite analysis. Approximately 2600 genes and 3898 transcripts were differentially expressed by at least 4-fold in drought-stressed potato tubers, with 75% and 69% being down-regulated, respectively. A further 229 small RNAs were implicated in gene regulation during drought. Expression of several small RNA clusters negatively correlated with expression of their six target patatin genes, suggesting involvement in the regulation of storage proteins during drought. The comparison of protein homologues between Solanum tuberosum L. and Arabidopsis thaliana L. indicated that down-regulated genes were associated with phenylpropanoid and carotenoid biosynthesis. As is indicative of reduced flow through the phenylpropanoid pathway, phenylalanine accumulated in drought-stressed tubers. This suggests that there may be nutritive implications to drought stress occurring during the potato tuber bulking phase in sensitive cultivars.
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Martell, Henry J., Avanthi Tayi Shah, Alex G. Lee, Bogdan Tanasa, Stanley G. Leung, Aviv Spillinger, Heng-Yi Liu, et al. "Abstract 54: Integrative analysis of whole-genome and RNA sequencing in high-risk pediatric malignancies." Cancer Research 82, no. 12_Supplement (June 15, 2022): 54. http://dx.doi.org/10.1158/1538-7445.am2022-54.
Повний текст джерелаАнотація:
Abstract The use of sequencing-based assays for clinical management of pediatric cancer patients has become increasingly common. However, for many pediatric patients, gene panel based sequencing tests yield few actionable results. Given the complex genomic alterations present in many pediatric cancers, especially high-risk solid tumors, we hypothesized that an unbiased approach might reveal more actionable findings and lead to a more comprehensive understanding of these diseases. To accomplish this, we integrated whole-genome sequencing (WGS) with RNAseq in the analysis of a pediatric oncology cohort, with a focus on longitudinal cases to capture potential tumor evolution in metastatic or treated cases. Our cohort consists of 269 high-risk pediatric oncology patients, including patients with relapsed/refractory disease, metastatic disease at diagnosis, prior cancer history, a rare diagnosis, or an estimated overall survival <50%. Solid tumors, CNS tumors, and leukemia/lymphomas are all represented. In total, 391 samples were characterized using WGS (tumor ~60X; germline ~30X) and/or RNAseq (tumor, polyA selected, ≥20 million reads). For 85 of these patients, multiple samples were collected at different time points (diagnosis, resection, relapse, etc.) to identify changes in the cancer over time. If panel testing was performed as part of their clinical care, a comparison to the integrated WGS/RNA analysis was made. WGS was used to identify variants (SNVs), structural rearrangements (SVs), mutational signatures, and copy-number alterations (CNAs). RNAseq was used to identify gene expression outliers, gene fusions, and confirm the expression of variants identified using WGS. The combination of WGS and RNAseq was then used to identify and prioritize potentially actionable variants for each patient. Our results show that the integration of WGS and RNAseq can provide more and higher-quality actionable information than either modality alone, whilst also capturing the majority of actionable variants detected by panel sequencing. RNAseq identified not only druggable fusions and expression outliers, but also many rare and novel fusions. WGS provided fusion validation but highlighted the limitations of WGS alone in identifying fusions resulting from complex SVs. Conversely, WGS was adept at capturing genome-wide patterns of CNAs and loss of heterozygosity that are missed by gene-centric panels. Further RNAseq integration enabled prioritization of expressed SNVs as well as CNAs and SVs that significantly alter gene expression. We also used WGS to extract mutational signatures and tracked their evolution across longitudinal samples. We found potentially biologically significant differences in therapy-induced mutations caused by platinum and alkylating agents. Our unbiased approach has enabled further discovery that advances our understanding of these rare and highly aggressive malignancies. Citation Format: Henry J. Martell, Avanthi Tayi Shah, Alex G. Lee, Bogdan Tanasa, Stanley G. Leung, Aviv Spillinger, Heng-Yi Liu, Inge Behroozfard, Phuong Dinh, Maria V. Pons Ventura, Florette K. Hazard, Arun Rangaswami, Sheri L. Spunt, Norman J. Lacayo, Tabitha Cooney, Jennifer G. Michlitsch, Anurag K. Agrawal, Marcus R. Breese, E. Alejandro Sweet-Cordero. Integrative analysis of whole-genome and RNA sequencing in high-risk pediatric malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 54.
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Broich, Markus, Kerstin Rydzewski, Tamara L. McNealy, Reinhard Marre, and Antje Flieger. "The Global Regulatory Proteins LetA and RpoS Control Phospholipase A, Lysophospholipase A, Acyltransferase, and Other Hydrolytic Activities of Legionella pneumophila JR32." Journal of Bacteriology 188, no. 4 (February 15, 2006): 1218–26. http://dx.doi.org/10.1128/jb.188.4.1218-1226.2006.
Повний текст джерелаАнотація:
ABSTRACT Legionella pneumophila possesses a variety of secreted and cell-associated hydrolytic activities that could be involved in pathogenesis. The activities include phospholipase A, lysophospholipase A, glycerophospholipid:cholesterol acyltransferase, lipase, protease, phosphatase, RNase, and p-nitrophenylphosphorylcholine (p-NPPC) hydrolase. Up to now, there have been no data available on the regulation of the enzymes in L. pneumophila and no data at all concerning the regulation of bacterial phospholipases A. Therefore, we used L. pneumophila mutants in the genes coding for the global regulatory proteins RpoS and LetA to investigate the dependency of hydrolytic activities on a global regulatory network proposed to control important virulence traits in L. pneumophila. Our results show that both L. pneumophila rpoS and letA mutants exhibit on the one hand a dramatic reduction of secreted phospholipase A and glycerophospholipid:cholesterol acyltransferase activities, while on the other hand secreted lysophospholipase A and lipase activities were significantly increased during late logarithmic growth phase. The cell-associated phospholipase A, lysophospholipase A, and p-NPPC hydrolase activities, as well as the secreted protease, phosphatase, and p-NPPC hydrolase activities were significantly decreased in both of the mutant strains. Only cell-associated phosphatase activity was slightly increased. In contrast, RNase activity was not affected. The expression of plaC, coding for a secreted acyltransferase, phospholipase A, and lysophospholipase A, was found to be regulated by LetA and RpoS. In conclusion, our results show that RpoS and LetA affect phospholipase A, lysophospholipase A, acyltransferase, and other hydrolytic activities of L. pneumophila in a similar way, thereby corroborating the existence of the LetA/RpoS regulation cascade.