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Pettit Kneller, Elizabeth L., John H. Connor, and Douglas S. Lyles. "hnRNPs Relocalize to the Cytoplasm following Infection with Vesicular Stomatitis Virus." Journal of Virology 83, no. 2 (November 12, 2008): 770–80. http://dx.doi.org/10.1128/jvi.01279-08.
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ABSTRACT Vesicular stomatitis virus (VSV) matrix protein inhibits nuclear-cytoplasmic mRNA transport. The goal of this work is to determine whether VSV inhibits the nuclear-cytoplasmic transport of heterogeneous ribonucleoproteins (hnRNPs), which are thought to serve as mRNA export factors. Confocal microscopy experiments showed that hnRNPA1, hnRNPK, and hnRNPC1/C2, but not hnRNPB1 or lamin A/C, are relocalized to the cytoplasm during VSV infection. We determined whether protein import is inhibited by VSV by transfecting cells with a plasmid encoding enhanced green fluorescent protein (EGFP) tagged with either the M9 nuclear localization sequence (NLS) or the classical NLS. These experiments revealed that both the M9 NLS and the classical NLS are functional during VSV infection. These data suggest that the inhibition of protein import is not responsible for hnRNP relocalization during VSV infection but that hnRNP export is enhanced. We found that hnRNPA1 relocalization was significantly reduced following the silencing of the mRNA export factor Rae1, indicating that Rae1 is necessary for hnRNP export. In order to determine the role of hnRNPA1 in VSV infection, we silenced hnRNPA1 in HeLa cells and assayed three aspects of the viral life cycle: host protein synthesis shutoff concurrent with the onset of viral protein synthesis, replication by plaque assay, and cell killing. We observed that host shutoff and replication are unaffected by the reduction in hnRNPA1 but that the rate of VSV-induced apoptosis is slower in cells that have reduced hnRNPA1. These data suggest that VSV promotes hnRNPA1 relocalization in a Rae1-dependent manner for apoptotic signaling.
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Komuro, Riho, Yuka Honda, Motoaki Yanaizu, Masami Nagahama, and Yoshihiro Kino. "Alzheimer’s Disease-Associated Alternative Splicing of CD33 Is Regulated by the HNRNPA Family Proteins." Cells 12, no. 4 (February 13, 2023): 602. http://dx.doi.org/10.3390/cells12040602.
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Genetic variations of CD33 have been implicated as a susceptibility factor of Alzheimer’s disease (AD). A polymorphism on exon 2 of CD33, rs12459419, affects the alternative splicing of this exon. The minor allele is associated with a reduced risk of AD and promotes the skipping of exon 2 to produce a shorter CD33 isoform lacking the extracellular ligand-binding domain, leading to decreased suppressive signaling on microglial activity. Therefore, factors that regulate the splicing of exon 2 may alter the disease-associated properties of CD33. Herein, we sought to identify the regulatory proteins of CD33 splicing. Using a panel of RNA-binding proteins and a human CD33 minigene, we found that exon 2 skipping of CD33 was promoted by HNRNPA1. Although the knockdown of HNRNPA1 alone did not reduce exon 2 skipping, simultaneous knockdown of HNRNPA1 together with that of HNRNPA2B1 and HNRNPA3 promoted exon 2 inclusion, suggesting functional redundancy among HNRNPA proteins. Similar redundant regulation by HNRNPA proteins was observed in endogenous CD33 of THP-1 and human microglia-like cells. Although mouse Cd33 showed a unique splicing pattern of exon 2, we confirmed that HNRNPA1 promoted the skipping of this exon. Collectively, our results revealed novel regulatory relationships between CD33 and HNRNPA proteins.
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Cloe, Adam, Li Chen, Yuan Li, Hongtao Liu, and Jason X. Cheng. "Identification of Specific Hnrnps As Novel Therapeutic Targets and Responsive Indicators of KPT330 (selinexor) in Leukemia." Blood 128, no. 22 (December 2, 2016): 1657. http://dx.doi.org/10.1182/blood.v128.22.1657.1657.
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Abstract Background: Activenuclear-cytoplasmic shuttling of proteins and RNAs, such as heterogeneous ribonucleoproteins (hnRNPs), is essential for the normal function and survival of eukaryotic cells and tumorigenesis (Dreyfuss et al. 1993 Annu Rev Biochem 62, 289; Gorlich and Mattaj 1996 Science 271, 1513). Up-regulation of exportin 1 (XPO1)/chromosomal maintenance 1 (CRM1), a member of the karyopherin-β family of nuclear export receptor proteins, has been implicated in solid and hematologic malignancies (Kau Kau et al. 2004).Selinexor (KPT-330) has been shown to be able block in vitro and in vivo XPO1/CRM1 functions and is currently in phase-II/IIb clinical trials for treatment of hematologic and solid tumors (Senapedis et al., 2014 Nat Rev Cancer 4, 106). However, the mechanisms underlying the selectivity and efficacy of selinexor are incompletely understood, and no biomarkers are currently available to predict clinical responses to selinexor in clinical settings. In this study, we focus on determining the effects of selinexor on the nuclear-cytoplasmic shuttling of hnRNPs, particularly hnRNPK and hnRNPA1, to elucidate the roles of the hnRNPs in the regulation of selectivity and efficacy of selinexor in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Method:We performed growth inhibition/killing assays, histopathologic evaluations, immunohistochemical studies, subcellular fraction western blotting, super-resolution stimulated emission depletion (STED) confocal microcopy and siRNA knockdown experiments. Results: Our in vitro experiments demonstrate a marked increase in XPO1/CRM1 protein and decrease in TP53 in our azacitidine-resistant MDS/AML cell lines compared to our azacitidine-sensitive MDS/AML cell lines. Selinexor treatment efficiently blocks export of hnRNP K from nuclei and increased nuclear accumulation of hnRNPK and inhibits MDS/AML cell growth, while the protein levels of XPO1/CRM1 and TP53 remain unchanged. Our experiments using clinical bone marrow specimens show no significant difference in the total protein level or nuclear accumulation of XPO1/CRM1 between the normal control and MDS or AML bone marrow specimens. In contrast, a strong positive correlation between MDS/AML disease progression and hnRNPK protein accumulation is observed in those clinical specimens. We have extended our experiments to clinical bone marrow specimens from a small cohort in a clinical trial for selinexor in AML at the University of Chicago (NCT02573363). In our small cohort, 5 patients responded to selinexor, 4 patients did not respond and 1 had a partial response. All 5 responders show a striking decrease in their bone marrow blast percentage from their pre-treatment marrows (average blast percentage 37.4%) to their post-treatment (average blast percentage 1.8%). Non-responders show no such difference in pre and post-treatment blast percentage (56.3 and 57.1%, respectively). Importantly, our experiments demonstrate a marked difference in the protein accumulation and subcellular localization of hnRNPK and hnRNPA1, another member of the hnRNP family, between selinexor-responder and selinexor-non-responder bone marrow specimens. Specifically, selinexor responders had much higher levels of hnRNPK and hnRNPA1 proteins in their pre-treatment bone marrows than non-responders, despite the fact that the latter had higher bone marrow blast percentages on average. There is markedly reduced accumulation of hnRNPK and hnRNPA1 in the post-selinexor treatment bone marrow specimens from the responders, but not the non-responders, suggesting these hnRNPs as key therapeutic targets for selinexor in MDS and AML. In contrast, no significant change in XPO1/CRM1 protein levels is observed in the selinexor-responder vs. selinexor-non-responder bone marrow specimens. Conclusion:Our data have revealed a novel drug-action mechanism by which selinexor impairs the nuclear-cytoplasmic shuttling of hnRNPK and hnRNPA1 in MDS and AML cells. Differential expression and localization of these hnRNPs in normal vs. MDS vs. AML cells may provide the rationale for the preferential killing of leukemia cells by selinexor. Our data also suggest the possibility to develop novel hnRNP-based biomarkers to predict the response to selinexor in clinical settings. Disclosures Liu: Karyopharm: Research Funding; BMS: Research Funding.
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Rothzerg, Emel, Wenyu Feng, Dezhi Song, Hengyuan Li, Qingjun Wei, Archa Fox, David Wood, Jiake Xu, and Yun Liu. "Single-Cell Transcriptome Analysis Reveals Paraspeckles Expression in Osteosarcoma Tissues." Cancer Informatics 21 (January 2022): 117693512211401. http://dx.doi.org/10.1177/11769351221140101.
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Nuclear paraspeckles are subnuclear bodies contracted by nuclear-enriched abundant transcript 1 (NEAT1) long non-coding RNA, localised in the interchromatin space of mammalian cell nuclei. Paraspeckles have been critically involved in tumour progression, metastasis and chemoresistance. To this date, there are limited findings to suggest that paraspeckles, NEAT1 and heterogeneous nuclear ribonucleoproteins (hnRNPs) directly or indirectly play roles in osteosarcoma progression. Herein, we analysed NEAT1, paraspeckle proteins (SFPQ, PSPC1 and NONO) and hnRNP members (HNRNPK, HNRNPM, HNRNPR and HNRNPD) gene expression in 6 osteosarcoma tumour tissues using the single-cell RNA-sequencing method. The normalised data highlighted that the paraspeckles transcripts were highly abundant in osteoblastic OS cells, except NEAT1, which was highly expressed in myeloid cell 1 and 2 subpopulations.
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White, Theresa L., Matthew Gable, Ye Jin, and Penelope Morel. "Understanding how AKT phosphorylation of hnRNPA1 modulates T cell fate and function." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 115.21. http://dx.doi.org/10.4049/jimmunol.202.supp.115.21.
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Abstract T regulatory cells (Treg) play a significant role in maintaining self-tolerance and preventing autoimmune diseases. We and others have shown that low dose favors Treg and T helper (Th) 2 cell differentiation, while high Ag dose stimulation activates the PI3K/Akt/mTOR pathway, favoring inflammatory Th1 and Th17 cell differentiation (Tconv). Differences in PI3K/Akt/mTOR signaling not only affects T cell fate but our research shows that Akt phosphorylation of the RNA-binding protein, (RBP) heterogeneous nuclear ribonucleoprotein (hnRNP) A1, is dependent on TCR signal strength. RBPs such as hnRNPA1 are emerging as regulators of RNA processing and stability in immune cells, and the effect of RBP on T cell differentiation is a growing subject of interest. We have shown hnRNPA1 is required for optimal Treg differentiation by performing knockdown experiments, and our present research is focused on identifying a role for Akt phosphorylation in hnRNPA1 function. HnRNPA1 is known to have a single Akt phosphorylation site at S199 and our lab has generated a new mutant mouse model, hnRNPA1-S199A (mA1). This mutation affects the ability of Akt to phosphorylate hnRNPA1 in all immune cells. Using Cytek’s Aurora flow cytometer we characterized the immune cell populations of mA1 at steady state. Preliminary data do not indicate any major changes in innate immune and B cells populations at steady state. We observed modest changes in CD4 T cell population frequencies at steady state. Current work using In vitro skewing suggests that Akt phosphorylation of hnRNPA1 influences Treg fate. This project suggests a novel mechanism by which Akt modulates T cell fate.
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White, Tristan L., Matthew Gable, Ye Jin, and Penelope A. Morel. "The Role of HnRNPA1 in T Cell-Mediated Gut Tolerance." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 56.12. http://dx.doi.org/10.4049/jimmunol.208.supp.56.12.
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Abstract Our previous research showed that Akt phosphorylation of the RNA-binding protein, (RBP) heterogeneous nuclear ribonucleoprotein (hnRNP) A1, is dependent on TCR signal strength, and occurs under conditions of induced T regulatory (Treg) cell differentiation. We have shown hnRNPA1 is required for optimal Treg differentiation by performing knockdown experiments, and our present research is focused on identifying a role for Akt phosphorylation in hnRNPA1 function. HnRNPA1 is phosphorylated by Akt at S199 and our lab has generated a new mutant mouse model, hnRNPA1-S199A (mA1), in which hnRNPA1 will no longer be Akt-phosphhorylated. Our initial characterization of mA1 mouse model failed to reveal major abnormalities in immune cells populations at steady state except for changes in the Treg proportion in the mesenteric lymph nodes. To investigate the effect of the mA1 on the development of oral tolerance we used an adoptive transfer model in which OT-II mA1 or OT-II WT naïve T cells were transferred into congenic strains and then the mice were given OVA food. Results indicate that mA1 OT-II T cells have a proliferation defect in vivo and we also observed a significant reduction in the induction of OVA-specific Treg in the mA1 T cells. Similar results were obtained when adoptively transferred OT-II mA1 T cells were challenged with limiting doses of specific peptide, given iv. RNASeq analysis of the transferred mA1 and WT T cells is being performed. These results suggest that Akt phosphorylation of hnRNPA1 is necessary for T cell response to low dose antigen and Treg induction in vivo. Our studies identify a new mechanism by which RBP influence T cell proliferation and Treg differentiation which has implications for tolerance to food antigens in the gut. Supported by NIH (F31-AI152320-02) NIH (R01-AI125513-03)
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Zhang, Li, Qishan Chen, Weiwei An, Feng Yang, Eithne Margaret Maguire, Dan Chen, Cheng Zhang, et al. "Novel Pathological Role of hnRNPA1 (Heterogeneous Nuclear Ribonucleoprotein A1) in Vascular Smooth Muscle Cell Function and Neointima Hyperplasia." Arteriosclerosis, Thrombosis, and Vascular Biology 37, no. 11 (November 2017): 2182–94. http://dx.doi.org/10.1161/atvbaha.117.310020.
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Objective— hnRNPA1 (heterogeneous nuclear ribonucleoprotein A1) plays a variety of roles in gene expression. However, little is known about the functional involvement of hnRNPA1 in vascular smooth muscle cell (VSMC) function and neointima hyperplasia. In this study, we have attempted to investigate the functional roles of hnRNPA1 in the contexts of VSMC function, injury-induced vessel remodeling, and human atherosclerotic lesions, as well as discern the molecular mechanisms involved. Approach and Results— hnRNPA1 expression levels were consistently modulated during VSMC phenotype switching and neointimal lesion formation induced by wire injury. Functional studies showed that VSMC-specific gene expression, proliferation, and migration were regulated by hnRNPA1. Our data show that hnRNPA1 exerts its effects on VSMC functions through modulation of IQGAP1 (IQ motif containing GTPase activating protein 1). Mechanistically, hnRNPA1 regulates IQGAP1 mRNA degradation through 2 mechanisms: upregulating microRNA-124 (miR-124) and binding to AU-rich element of IQGAP1 gene. Further evidence suggests that hnRNPA1 upregulates miR-124 by modulating miR-124 biogenesis and that IQGAP1 is the authentic target gene of miR-124. Importantly, ectopic overexpression of hnRNPA1 greatly reduced VSMC proliferation and inhibited neointima formation in wire-injured carotid arteries. Finally, lower expression levels of hnRNPA1 and miR-124, while higher expression levels of IQGAP1, were observed in human atherosclerotic lesions. Conclusions— Our data show that hnRNPA1 is a critical regulator of VSMC function and behavior in the context of neointima hyperplasia, and the hnRNPA1/miR-124/IQGAP1 regulatory axis represents a novel therapeutic target for the prevention of cardiovascular diseases.
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Toosaranont, Jarichad, Sukanya Ruschadaariyachat, Warasinee Mujchariyakul, Jantarika Kumar Arora, Varodom Charoensawan, Bhoom Suktitipat, Thomas N. Palmer, Sue Fletcher, Steve D. Wilton, and Chalermchai Mitrpant. "Antisense Oligonucleotide Induction of the hnRNPA1b Isoform Affects Pre-mRNA Splicing of SMN2 in SMA Type I Fibroblasts." International Journal of Molecular Sciences 23, no. 7 (April 1, 2022): 3937. http://dx.doi.org/10.3390/ijms23073937.
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Spinal muscular atrophy (SMA) is a severe, debilitating neuromuscular condition characterised by loss of motor neurons and progressive muscle wasting. SMA is caused by a loss of expression of SMN1 that encodes the survival motor neuron (SMN) protein necessary for the survival of motor neurons. Restoration of SMN expression through increased inclusion of SMN2 exon 7 is known to ameliorate symptoms in SMA patients. As a consequence, regulation of pre-mRNA splicing of SMN2 could provide a potential molecular therapy for SMA. In this study, we explored if splice switching antisense oligonucleotides could redirect the splicing repressor hnRNPA1 to the hnRNPA1b isoform and restore SMN expression in fibroblasts from a type I SMA patient. Antisense oligonucleotides (AOs) were designed to promote exon 7b retention in the mature mRNA and induce the hnRNPA1b isoform. RT-PCR and western blot analysis were used to assess and monitor the efficiency of different AO combinations. A combination of AOs targeting multiple silencing motifs in hnRNPA1 pre-mRNA led to robust hnRNPA1b induction, which, in turn, significantly increased expression of full-length SMN (FL-SMN) protein. A combination of PMOs targeting the same motifs also strongly induced hnRNPA1b isoform, but surprisingly SMN2 exon 5 skipping was detected, and the PMO cocktail did not lead to a significant increase in expression of FL-SMN protein. We further performed RNA sequencing to assess the genome-wide effects of hnRNPA1b induction. Some 3244 genes were differentially expressed between the hnRNPA1b-induced and untreated SMA fibroblasts, which are functionally enriched in cell cycle and chromosome segregation processes. RT-PCR analysis demonstrated that expression of the master regulator of these enrichment pathways, MYBL2 and FOXM1B, were reduced in response to PMO treatment. These findings suggested that induction of hnRNPA1b can promote SMN protein expression, but not at sufficient levels to be clinically relevant.
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Fifita, Jennifer A., Katharine Y. Zhang, Jasmin Galper, Kelly L. Williams, Emily P. McCann, Alison L. Hogan, Neil Saunders, et al. "Genetic and Pathological Assessment of hnRNPA1, hnRNPA2/B1, and hnRNPA3 in Familial and Sporadic Amyotrophic Lateral Sclerosis." Neurodegenerative Diseases 17, no. 6 (2017): 304–12. http://dx.doi.org/10.1159/000481258.
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Möller, Katharina, Anna Lena Wecker, Doris Höflmayer, Christoph Fraune, Georgia Makrypidi-Fraune, Claudia Hube-Magg, Martina Kluth, et al. "Upregulation of the heterogeneous nuclear ribonucleoprotein hnRNPA1 is an independent predictor of early biochemical recurrence in TMPRSS2:ERG fusion-negative prostate cancers." Virchows Archiv 477, no. 5 (May 16, 2020): 625–36. http://dx.doi.org/10.1007/s00428-020-02834-4.
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Abstract Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) is a ubiquitous RNA splicing factor that is overexpressed and prognostically relevant in various human cancer types. To study the impact of hnRNPA1 expression in prostate cancer, we analyzed a tissue microarray containing 17,747 clinical prostate cancer specimens by immunohistochemistry. hnRNPA1 was expressed in normal prostate glandular cells but often overexpressed in cancer cells. hnRNPA1 immunostaining was interpretable in 14,258 cancers and considered strong in 33.4%, moderate in 45.9%, weak in 15.3%, and negative in 5.4%. Moderate to strong hnRNPA1 immunostaining was strongly linked to adverse tumor features including high classical and quantitative Gleason score, lymph node metastasis, advanced tumor stage, positive surgical margin, and early biochemical recurrence (p < 0.0001 each). The prognostic impact of hnRNPA1 immunostaining was independent of established preoperatively or postoperatively available prognostic parameters (p < 0.0001). Subset analyses revealed that all these associations were strongly driven by the fraction of cancers lacking the TMPRSS2:ERG gene fusion. Comparison with other key molecular data that were earlier obtained on the same TMA showed that hnRNPA1 overexpression was linked to high levels of androgen receptor (AR) expression (p < 0.0001) as well as presence of 9 of 11 chromosomal deletions (p < 0.05 each). A strong association between hnRNPA1 upregulation and tumor cell proliferation that was independent from the Gleason score supports a role for tumor cell aggressiveness. In conclusion, hnRNPA1 overexpression is an independent predictor of poor prognosis in ERG-negative prostate cancer. hnRNPA1 measurement, either alone or in combination, might provide prognostic information in ERG-negative prostate cancer.
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Yadav, Ajay. "HGG-27. HNRNPA1 SPLICED VARIANT SENSITIZATION EFFECT DISCLOSED IN GLIOMA CELLS." Neuro-Oncology 23, Supplement_1 (June 1, 2021): i22—i23. http://dx.doi.org/10.1093/neuonc/noab090.091.
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Abstract Glioblastoma is aggressive brain tumor. Glioma heterogeneity builds in hypoxic condition due to its intrinsic high apoptosis rate cause to develop a high selection clonal pressure. HnRNPA1 plays a key role in developing glycolytic tumor, shows its high expression exclusively in hypoxic glioma cells. Recently we observed one more spliced variant of hnRNPA1, encoding higher isoform, exclusively abundant in resistant glioma cell lines. Widely around the scientific community HnRNPA1 splice factor family protein was found distinctly regulating resistant glioma phenotype. To support our hypothesis, methodology we perform includes various apoptosis assays to critically understand hnRNPA1 spliced variant dependent pathway in Temozolomide resistant U87 glioma cells. Proteomic based apoptotic array and angiogenic array enable us to visualize selective knock down of hnRNPA1 has dominant role in promoting apoptotic cascade. Additionally, flow cytometry base annexin V-PI staining technique to understand early and late apoptosis was measured in selective hnRNPA1 spliced variant knockdown cells in presence or absence of PI3 kinase inhibitor wortmannin (5 micro molar). Results showed hnRNPA1 higher isoform knock down promotes more apoptosis compare to lower isoform. Interestingly, overexpression of HnRNPA1 higher isoform or lower isoform alone doesn’t promote apoptosis, however is prominently higher apoptosis in Bortezomib treated U87 glioma cells. These both isoforms are presently majorly in gliomas, but somehow for long was not recognized. Conclusion is to explore more related novel finding or therapeutic strategy to target higher isoform of hnRNPA1, using invivo mouse xenograft model.
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Yadav, Ajay. "BIOL-09. HNRNPA1 SPLICED VARIANT: KEY RESISTANT GENE SIGNATURE IN GLIOMAS." Neuro-Oncology 23, Supplement_1 (June 1, 2021): i4—i5. http://dx.doi.org/10.1093/neuonc/noab090.016.
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Abstract Glioblastoma is inevitably a recurrent cancer. Despite of recent advancement, temozolomide remain the prescribed lifeline drug, after the surgery. Inadvertently, MGMT (O6-methylguanine-DNA-methyltransferase) expression mechanistically linked with Temozolomide (alkylating drug) glioma resistant development. To understand the resistant against Temozolomide sought to deciphered, by making invitro drug resistant glioma cell lines. RNA seq analysis over a illumina platform; drug resistant glioma cell lines showed various critical key factor such as splice factor hnRNPA1 and deubiquitinating enzymes were showed to highly upregulated in resistant cell lines. Commonly, from our previous study, the stability of hnRNPA1 in presence of USP5 were showed to promote cell survival, whereas knocking down of USP5 significantly lower down the telomerase activity and NAD/NADH ratio enlarge. Furthermore, expression of MGMT was showed significantly downregulated in hnRNPA1 knock down T98G glioma cells, as well as in U87 Temozolomide resistant cells. Extrinsic apoptosis pathway was showed more prevalent in hnRNPA1 knock down glioma cells in presence of Trail ligand. Interestingly, we found one more spliced variants of hnRNPA1 exclusively expressing in drug resistant cells is new finding. Selectively knocking down of hnRNPA1 splice variant promotes apoptosis. RNA seq analysis followed the comparison between two hnRNPA1 spliced variant knock down, drug resistant glioma cell lines showed differentially expressed transcript support our finding to be distinctly regulated by hnRNPA1 spliced variants. Spliced variant of hnRNPA1 showed a potential therapeutic candidate signature.
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CHANG, Yan, Xiaofeng LU, and Jiaying QIU. "Compensatory expression regulation of highly homologous proteins HNRNPA1 and HNRNPA2." TURKISH JOURNAL OF BIOLOGY 45, no. 2 (April 20, 2021): 187–95. http://dx.doi.org/10.3906/biy-2010-29.
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Han, Xuesong, Xudong Xiang, Hongying Yang, Hongping Zhang, Shuang Liang, Jie Wei, and Jing Yu. "p300-Catalyzed Lysine Crotonylation Promotes the Proliferation, Invasion, and Migration of HeLa Cells via Heterogeneous Nuclear Ribonucleoprotein A1." Analytical Cellular Pathology 2020 (December 5, 2020): 1–6. http://dx.doi.org/10.1155/2020/5632342.
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Cervical carcinoma is the third most common cause of cancer in women with a significant challenge in clinical treatment. Human papillomavirus (HPV) is strongly responsible for cervical carcinoma. Here, we show the increased expression level of heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) in HPV-associated cervical cancer cells including HeLa, Caski, and SiHa cells, especially in HeLa cells. We provide the evidence that the expression of HNRNPA1 is closely related to HeLa cell proliferation, invasion, and migration. Emerging evidence show that histone modifications account for gene expression. Moreover, our results indicate that HNRNPA1 could be regulated by p300 through p300-mediated lysine crotonylation. Inhibition of p300 downregulated both the lysine crotonylation level and the HNRNPA1 expression. And p300-mediated lysine crotonylation participates in the regulation of HNRNPA1 on HeLa cell proliferation, invasion, and migration. Collectively, our study uncovers that p300-mediated lysine crotonylation enhances expression of HNRNPA1 to promote the proliferation, invasion, and migration of HeLa cells.
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Sui, Jiang-Dong, Zheng Tang, Benjamin P. C. Chen, Ping Huang, Meng-Qi Yang, Nuo-Han Wang, Hao-Nan Yang, et al. "Protein Phosphatase 2A–Dependent Mitotic hnRNPA1 Dephosphorylation and TERRA Formation Facilitate Telomere Capping." Molecular Cancer Research 20, no. 4 (December 21, 2021): 583–95. http://dx.doi.org/10.1158/1541-7786.mcr-21-0581.
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Abstract The heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), telomeric repeat-containing RNA (TERRA), and protection of telomeres 1 (POT1) have been reported to orchestrate to displace replication protein A (RPA) from telomeric overhangs, ensuring orderly telomere replication and capping. Our previous studies further demonstrated that DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-dependent hnRNPA1 phosphorylation plays a crucial role in the promotion of hnRNPA1 binding to telomeric overhangs and RPA displacement during G2–M phases. However, it is unclear that how the subsequent exchange between hnRNPA1 and POT1 is orchestrated. Here we report that the protein phosphatase 2A (PP2A) depends on its scaffold subunit, which is called PPP2R1A, to interact with and dephosphorylate hnRNPA1 in the late M phase. Furthermore, PP2A-mediated hnRNPA1 dephosphorylation and TERRA accumulation act in concert to promote the hnRNPA1-to-POT1 switch on telomeric single-stranded DNA. Consequently, defective PPP2R1A results in ataxia telangiectasia and Rad3-related (ATR)-mediated DNA damage response at telomeres as well as induction of fragile telomeres. Combined inhibition of ATR and PP2A induces entry into a catastrophic mitosis and leads to synthetic lethality of tumor cells. In addition, PPP2R1A levels correlate with clinical stages and prognosis of multiple types of cancers. Taken together, our results indicate that PP2A is critical for telomere maintenance. Implications: This study demonstrates that the PP2A-dependent hnRNPA1 dephosphorylation and TERRA accumulation facilitates the formation of the protective capping structure of newly replicated telomeres, thus exerting essential oncogenic role in tumorigenesis.
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Hay, David C., Graham D. Kemp, Catherine Dargemont, and Ronald T. Hay. "Interaction between hnRNPA1 and IκBα Is Required for Maximal Activation of NF-κB-Dependent Transcription." Molecular and Cellular Biology 21, no. 10 (May 15, 2001): 3482–90. http://dx.doi.org/10.1128/mcb.21.10.3482-3490.2001.
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ABSTRACT Transcriptional activation of NF-κB is mediated by signal-induced phosphorylation and degradation of its inhibitor, IκBα. NF-κB activation induces a rapid resynthesis of IκBα which is responsible for postinduction repression of transcription. Following resynthesis, IκBα translocates to the nucleus, removes template bound NF-κB, and exports NF-κB to the cytoplasm in a transcriptionally inactive form. Here we demonstrate that IκBα interacts directly with another nucleocytoplasmic shuttling protein, hnRNPA1, both in vivo and in vitro. This interaction requires one of the N-terminal RNA binding domains of hnRNPA1 and the C-terminal region of IκBα. Cells lacking hnRNPA1 are defective in NF-κB-dependent transcriptional activation, but the defect in these cells is complemented by ectopic expression of hnRNPA1. hnRNPA1 expression in these cells increased the amount of IκBα degradation, compared to that of the control cells, in response to activation by Epstein-Barr virus latent membrane protein 1. Thus in addition to regulating mRNA processing and transport, hnRNPA1 also contributes to the control of NF-κB-dependent transcription.
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Kaur, Ramandeep, Jyoti Batra, Olga Stuchlik, Matthew S. Reed, Jan Pohl, Suryaprakash Sambhara, and Sunil Kumar Lal. "Heterogeneous Ribonucleoprotein A1 (hnRNPA1) Interacts with the Nucleoprotein of the Influenza a Virus and Impedes Virus Replication." Viruses 14, no. 2 (January 20, 2022): 199. http://dx.doi.org/10.3390/v14020199.
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Influenza A virus (IAV), like other viruses, depends on the host cellular machinery for replication and production of progeny. The relationship between a virus and a host is complex, shaped by many spatial and temporal interactions between viral and host proteome, ultimately dictating disease outcome. Therefore, it is imperative to identify host-virus interactions as crucial determinants of disease pathogenies. Heterogeneous ribonucleoprotein A1 (hnRNPA1) is an RNA binding protein involved in the life cycle of many DNA and RNA viruses; however, its role in IAV remains undiscovered. Here we report that human hnRNPA1 physically interacts with the nucleoprotein (NP) of IAV in mammalian cells at different time points of the viral replication cycle. Temporal distribution studies identify hnRNPA1 and NP co-localize in the same cellular milieu in both nucleus and mitochondria in NP-transfected and IAV-infected mammalian cells. Interestingly, hnRNPA1 influenced NP gene expression and affected viral replication. Most importantly, hnRNPA1 knockdown caused a significant increase in NP expression and enhanced viral replication (93.82%) in IAV infected A549 cells. Conversely, hnRNPA1 overexpression reduced NP expression at the mRNA and protein levels and impeded virus replication by (60.70%), suggesting antagonistic function. Taken together, results from this study demonstrate that cellular hnRNPA1 plays a protective role in the host hitherto unknown and may hold potential as an antiviral target to develop host-based therapeutics against IAV.
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Hsu, Ming-Chuan, Mei-Ren Pan, Pei-Yi Chu, Ya-Li Tsai, Chia-Hua Tsai, Yan-Shen Shan, Li-Tzong Chen, and Wen-Chun Hung. "Protein Arginine Methyltransferase 3 Enhances Chemoresistance in Pancreatic Cancer by Methylating hnRNPA1 to Increase ABCG2 Expression." Cancers 11, no. 1 (December 20, 2018): 8. http://dx.doi.org/10.3390/cancers11010008.
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Pancreatic cancer is poorly responsive to chemotherapy due to intrinsic or acquired resistance. Our previous study showed that epigenetic modifying enzymes including protein arginine methyltransferase 3 (PRMT3) are dysregulated in gemcitabine (GEM)-resistant pancreatic cancer cells. Here, we attempt to elucidate the role of PRMT3 in chemoresistance. Overexpression of PRMT3 led to increased resistance to GEM in pancreatic cancer cells, whereas reduction of PRMT3 restored GEM sensitivity in resistant cells. We identified a novel PRMT3 target, ATP-binding cassette subfamily G member 2 (ABCG2), which is known to play a critical role in drug resistance. PRMT3 overexpression upregulated ABCG2 expression by increasing its mRNA stability. Mass spectrometric analysis identified hnRNPA1 as a PRMT3 interacting protein, and methylation of hnRNPA1 at R31 by PRMT3 in vivo and in vitro. The expression of methylation-deficient hnRNPA1-R31K mutant reduced the RNA binding activity of hnRNPA1 and the expression of ABCG2 mRNA. Taken together, this provides the first evidence that PRMT3 methylates the RNA recognition motif (RRM) of hnRNPA1 and promotes the binding between hnRNPA1 and ABCG2 to enhance drug resistance. Inhibition of PRMT3 could be a novel strategy for the treatment of GEM-resistant pancreatic cancer.
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Liu, Xiao, and Yan Xu. "HnRNPA1 Specifically Recognizes the Base of Nucleotide at the Loop of RNA G-Quadruplex." Molecules 23, no. 1 (January 22, 2018): 237. http://dx.doi.org/10.3390/molecules23010237.
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Human telomere RNA performs various cellular functions, such as telomere length regulation, heterochromatin formation, and end protection. We recently demonstrated that the loops in the RNA G-quadruplex are important in the interaction of telomere RNA with heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1). Here, we report on a detailed analysis of hnRNPA1 binding to telomere RNA G-quadruplexes with a group of loop variants using an electrophoretic mobility shift assay (EMSA) and circular dichroism (CD) spectroscopy. We found that the hnRNPA1 binds to RNA G-quadruplexes with the 2’-O-methyl and DNA loops, but fails to bind with the abasic RNA and DNA loops. These results suggested that hnRNPA1 binds to the loop of the RNA G-quadruplex by recognizing the base of the loop’s nucleotides. The observation provides the first evidence that the base of the loop’s nucleotides is a key factor for hnRNPA1 specifically recognizing the RNA G-quadruplex.
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White, Theresa L., Matthew Gable, Ye Jin, and Penelope Morel. "Understanding the role of hnRNPA1 on T cell differentiation." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 98.30. http://dx.doi.org/10.4049/jimmunol.206.supp.98.30.
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Abstract Regulatory T cells (Treg) play a critical role in preventing autoimmunity diseases and maintaining tolerance in various tissues, particularly the gut. Peripheral derived Tregs (pTregs) are especially crucial in gut homeostasis and tolerance to commensal and food antigens. We have previously shown that knockdown of the RNA-binding protein, heterogeneous nuclear ribonucleoprotein (hnRNP) A1, reduces in vitro pTreg induction upon low TCR stimulation. In addition, we have shown that, under conditions of low TCR stimulation, in which pTregs are induced, hnRNP A1 is phosphorylated by Akt. In order to explore the impact of hnRNP A1 phosphorylation by Akt on pTregs induction we have generated a mutant mouse model, hnRNPA1-S199 in which the known Akt phosphorylation site on hnRNP A1 is mutated to Alanine. We have examined the induction of pTregs in vivo using an adoptive transfer model of OT-II TCR transgenic mutant (hnRNPA1-S199A) and wild-type naïve CD4 T cells followed by oral OVA administration. In addition, we are examining the induction of pTregs in vitro using OVA peptide presented by wild-type and mutant (antigen presenting cells) APC from the spleen. Preliminary data showed a decrease in pTreg induction and proliferation when naïve mutant T cells are stimulated either in vitro or in vivo with OVA. Furthermore, we observe that mutant APC have a reduced ability to induce proliferation and pTreg induction in both mutant and WT T cells. These data suggest that hnRNP A1 has important functions in both T cells induction and antigen presentation.
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Fung, Lianna, Herlinda Guzman, Evgueni Sevrioukov, Adam Idica, Eddie Park, Aurore Bochnakian, Iben Daugaard, et al. "miR-128 Restriction of LINE-1 (L1) Retrotransposition Is Dependent on Targeting hnRNPA1 mRNA." International Journal of Molecular Sciences 20, no. 8 (April 21, 2019): 1955. http://dx.doi.org/10.3390/ijms20081955.
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The majority of the human genome is made of transposable elements, giving rise to interspaced repeats, including Long INterspersed Element-1s (LINE-1s or L1s). L1s are active human transposable elements involved in genomic diversity and evolution; however, they can also contribute to genomic instability and diseases. L1s require host factors to complete their life cycles, whereas the host has evolved numerous mechanisms to restrict L1-induced mutagenesis. Restriction mechanisms in somatic cells include methylation of the L1 promoter, anti-viral factors and RNA-mediated processes such as small RNAs. microRNAs (miRNAs or miRs) are small non-coding RNAs that post-transcriptionally repress multiple target genes often found in the same cellular pathways. We have recently established that miR-128 functions as a novel restriction factor inhibiting L1 mobilization in somatic cells. We have further demonstrated that miR-128 functions through a dual mechanism; by directly targeting L1 RNA for degradation and indirectly by inhibiting a cellular co-factor which L1 is dependent on to transpose to new genomic locations (TNPO1). Here, we add another piece to the puzzle of the enigmatic L1 lifecycle. We show that miR-128 also inhibits another key cellular factor, hnRNPA1 (heterogeneous nuclear ribonucleoprotein A1), by significantly reducing mRNA and protein levels through direct interaction with the coding sequence (CDS) of hnRNPA1 mRNA. In addition, we demonstrate that repression of hnRNPA1 using hnRNPA1-shRNA significantly decreases de novo L1 retro-transposition and that induced hnRNPA1 expression enhances L1 mobilization. Furthermore, we establish that hnRNPA1 is a functional target of miR-128. Finally, we determine that induced hnRNPA1 expression in miR-128-overexpressing cells can partly rescue the miR-128-induced repression of L1′s ability to transpose to different genomic locations. Thus, we have identified an additional mechanism by which miR-128 represses L1 retro-transposition and mediates genomic stability.
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Li, Moyi, Yan Zhuang, Ranjan Batra, James D. Thomas, Mao Li, Curtis A. Nutter, Marina M. Scotti, et al. "HNRNPA1-induced spliceopathy in a transgenic mouse model of myotonic dystrophy." Proceedings of the National Academy of Sciences 117, no. 10 (February 21, 2020): 5472–77. http://dx.doi.org/10.1073/pnas.1907297117.
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Studies on myotonic dystrophy type 1 (DM1) have led to the RNA-mediated disease model for hereditary disorders caused by noncoding microsatellite expansions. This model proposes that DM1 disease manifestations are caused by a reversion to fetal RNA processing patterns in adult tissues due to the expression of toxic CUG RNA expansions (CUGexp) leading to decreased muscleblind-like, but increased CUGBP1/ETR3-like factor 1 (CELF1), alternative splicing activities. Here, we test this model in vivo, using the mouse HSALR poly(CUG) model for DM1 and recombinant adeno-associated virus (rAAV)-mediated transduction of specific splicing factors. Surprisingly, systemic overexpression of HNRNPA1, not previously linked to DM1, also shifted DM1-relevant splicing targets to fetal isoforms, resulting in more severe muscle weakness/myopathy as early as 4 to 6 wk posttransduction, whereas rAAV controls were unaffected. Overexpression of HNRNPA1 promotes fetal exon inclusion of representative DM1-relevant splicing targets in differentiated myoblasts, and HITS-CLIP of rAAV-mycHnrnpa1-injected muscle revealed direct interactions of HNRNPA1 with these targets in vivo. Similar to CELF1, HNRNPA1 protein levels decrease during postnatal development, but are elevated in both regenerating mouse muscle and DM1 skeletal muscle. Our studies suggest that CUGexp RNA triggers abnormal expression of multiple nuclear RNA binding proteins, including CELF1 and HNRNPA1, that antagonize MBNL activity to promote fetal splicing patterns.
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Murray, Dylan T., Xiaoming Zhou, Masato Kato, Siheng Xiang, Robert Tycko, and Steven L. McKnight. "Structural characterization of the D290V mutation site in hnRNPA2 low-complexity–domain polymers." Proceedings of the National Academy of Sciences 115, no. 42 (October 2, 2018): E9782—E9791. http://dx.doi.org/10.1073/pnas.1806174115.
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Human genetic studies have given evidence of familial, disease-causing mutations in the analogous amino acid residue shared by three related RNA binding proteins causative of three neurological diseases. Alteration of aspartic acid residue 290 of hnRNPA2 to valine is believed to predispose patients to multisystem proteinopathy. Mutation of aspartic acid 262 of hnRNPA1 to either valine or asparagine has been linked to either amyotrophic lateral sclerosis or multisystem proteinopathy. Mutation of aspartic acid 378 of hnRNPDL to either asparagine or histidine has been associated with limb girdle muscular dystrophy. All three of these aspartic acid residues map to evolutionarily conserved regions of low-complexity (LC) sequence that may function in states of either intrinsic disorder or labile self-association. Here, we present a combination of solid-state NMR spectroscopy with segmental isotope labeling and electron microscopy on the LC domain of the hnRNPA2 protein. We show that, for both the wild-type protein and the aspartic acid 290-to-valine mutant, labile polymers are formed in which the LC domain associates into an in-register cross-β conformation. Aspartic acid 290 is shown to be charged at physiological pH and immobilized within the polymer core. Polymers of the aspartic acid 290-to-valine mutant are thermodynamically more stable than wild-type polymers. These observations give evidence that removal of destabilizing electrostatic interactions may be responsible for the increased propensity of the mutated LC domains to self-associate in disease-causing conformations.
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Kim, Young-Jon, Byoung-Ryun Kim, Jae-Suk Ryu, Gyeong-Ok Lee, Hak-Ryul Kim, Keum-Ha Choi, Jae-Won Ryu, et al. "HNRNPA1, a Splicing Regulator, Is an Effective Target Protein for Cervical Cancer Detection: Comparison With Conventional Tumor Markers." International Journal of Gynecologic Cancer 27, no. 2 (February 2017): 326–31. http://dx.doi.org/10.1097/igc.0000000000000868.
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ObjectiveHeterogeneous nuclear ribonucleoprotein A1 (HNRNPA1), serine/arginine-rich splicing factor 1 (SRSF1), and SRSF3 are splicing regulators associated with oncogenesis. However, the alterations of SF proteins and their diagnostic values in cervical cancer are unclear. To apply SFs clinically, effective marker selection and characterization of the target organ properties are essential.Materials and MethodsWe concurrently analyzed HNRNPA1, SRSF1, SRSF3, and the conventional tumor markers squamous cell carcinoma antigen (SCCA) and carcinoembryonic antigen (CEA) in cervical tissue samples (n = 127) using semiquantitative immunoblotting. In addition, we compared them with p16 (cyclin-dependent kinase inhibitor 2A [CDKN2A]), which has shown high diagnostic efficacy in immunohistochemical staining studies and has been proposed as a candidate protein for point-of-care screening biochemical tests of cervical neoplasia.ResultsHNRNPA1, higher molecular weight forms of SRSF1 (SRSF1-HMws), SRSF3, CEA, and p16 levels were higher (P < 0.05) in cervical carcinoma tissue samples than in nontumoral cervical tissue samples. However, the levels of SRSF1-Total (sum of SRSF1-HMws and a lower molecular weight form of SRSF1) and SCCA, a commonly used cervical tumor marker, were not different between carcinoma and nontumoral tissue samples. In paired sample comparisons, HNRNPA1 (94%) showed the highest incidence of up-regulation (carcinoma/nontumor, >1.5) in cervical carcinoma, followed by p16 (84%), SRSF1-HMws (69%), SRSF3 (66%), CEA (66 %), SCCA (32%), and SRSF1-Total (31%). HNRNPA1 (92%) and p16 (91%) presented the two highest diagnostic accuracies for cervical carcinoma, which were superior to those of SRSF3 (75%), SRSF1-HMws (72%), CEA (72%), SCCA (59%), and SRSF1-Total (55%).ConclusionsOur results identified that HNRNPA1 is the best diagnostic marker among the SFs and conventional markers given its excellent diagnostic efficacy for cervical carcinoma, and it has a p16-comparable diagnostic value. We suggest that HNRNPA1 is an additional effective target protein for developing cervical cancer detection tools.
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Fang, Jing, Lyndsey Bolanos, Kwang-Min Choi, Xiaona Liu, Susanne Christie, Shailaja Akunuru, Rupali Kumar, et al. "Ubiquitin Editing of a Spliceosome Auxiliary Factor By TRAF6 Links Chronic TLR Signaling with Hematopoietic Defects and Myelodysplasia." Blood 126, no. 23 (December 3, 2015): 143. http://dx.doi.org/10.1182/blood.v126.23.143.143.
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Abstract Toll-like receptors (TLR) are known for regulating myeloid homeostasis and response to infection, but chronic activation of TLR pathways can also lead to hematopoietic stem and progenitor cell (HSPC) dysfunction. Furthermore, mutations that lead to constitutive activation of TLR pathways contribute to premalignant hematologic conditions, such as myelodysplastic syndromes (MDS); however, the underlying cellular and molecular mechanisms are unknown. As a means of chronically activating TLR signaling within HSPCs, we generated a mouse model by elevating expression of TRAF6 in hematopoietic cells (Vav-TRAF6). TRAF6 is a downstream TLR-effector with ubiquitin (Ub) E3 ligase activity, and is overexpressed in MDS HSPCs. Vav-TRAF6 mice developed progressive leukopenia and anemia, and exhibited myeloid skewing and dysplasia. Eventually, over half of Vav-TRAF6 mice succumbed to a bone marrow (BM) failure associated with MDS. Despite increased frequencies of immunophenotypic HSPCs in the BM, Vav-TRAF6 HSPCs are functionally defective as evidenced by impaired colony formation and reduced in vivo competitiveness. The hematopoietic phenotype due to TRAF6 overexpression was still manifest upon transplantation, indicating that the effect is hematopoietic cell intrinsic. Consistent with the cellular effects observed with chronic TLR activation, elevated TRAF6 expression results in MDS/BMF by altering intrinsic HSPC properties. Gene expression and exon level analyses revealed that Vav-TRAF6 HSPCs exhibit discrete and durable alterations in RNA splicing patterns. The family of small G-protein GTPases emerged as a relevant pathway whose activity is affected by missplicing of Arhgap1, a GTPase activating protein. Aberrant skipping of Arhgap1 exon 2 resulted in reduced Arhgap1 protein and constitutive Cdc42 GTPase activation. Inhibition of Cdc42 activity with a pharmacological inhibitor partially reversed myeloid-biased differentiation of Vav-TRAF6 HSPCs in vivo, indicating that missplicing of Arhgap1 and increased Cdc42 activity accounts for several HSPC defects. To identify the mechanism underlying TRAF6-induced RNA splicing, we employed a global Ub-enrichment screen for novel TRAF6 substrates, and uncovered hnRNPA1, an RNA-binding protein that regulates exon usage. hnRNPA1 is ubiquitinated by TRAF6 adjacent to and within its first RNA-binding domain. hnRNPA1 binding sites were significantly enriched within misspliced exons in Vav-TRAF6 HSPCs and in primary human AML samples with elevated TRAF6 expression, indicating that TRAF6 overexpression induces exon skipping via hnRNPA1. The requirement of hnRNPA1 in TRAF6-induced exon skipping was confirmed as knockdown of hnRNPA1 significantly reduced Arhgap1 exon 2 skipping in Vav-TRAF6 HSPC. Moreover, depletion of hnRNPA1 reversed Vav-TRAF6 hematopoietic defects in vivo, unequivocally validating the importance of hnRNPA1 in TRAF6-mediated exon skipping and function of HSPCs. Our findings uncover a novel mechanism by which sustained TLR signaling, via TRAF6-mediated ubiquitination of hnRNPA1, alters RNA splicing and contributes to MDS-associated HSPC defects in part by activating Cdc42. These results indicate a novel function for Ub signaling in coordinating transcriptional initiation and alternative splicing by TLR signaling pathway within the immune system and in premalignant hematologic diseases, such as MDS. Disclosures Starczynowski: Celgene Corporation: Research Funding.
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Pham, Thao N. D., Sophie Stempel, Mario A. Shields, Christina Spaulding, Krishan Kumar, David J. Bentrem, Maria Matsangou, and Hidayatullah G. Munshi. "Quercetin Enhances the Anti-Tumor Effects of BET Inhibitors by Suppressing hnRNPA1." International Journal of Molecular Sciences 20, no. 17 (September 2, 2019): 4293. http://dx.doi.org/10.3390/ijms20174293.
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Bromodomain and extraterminal domain (BET) proteins, which are important epigenetic readers, are often dysregulated in cancer. While a number of BET inhibitors are currently in early phase clinical trials, BET inhibitors show limited single-agent activity. The purpose of this study is to determine if Quercetin, a naturally occurring polyphenolic flavonoid often found abundant in fruits and vegetables, can enhance the anti-tumor effects of BET inhibitors. The efficacy of the combination was evaluated in vitro and in a xenograft model of pancreatic cancer. Co-treatment with BET inhibitors and Quercetin promoted apoptosis, decreased sphere-forming ability by cancer cells, and decreased cell proliferation. We found that hnRNPA1, a nuclear protein known to control mRNA export and mRNA translation of anti-apoptotic proteins, mediates some anti-tumor effects by Quercetin. Additionally, we show that combining BET inhibitors with Quercetin or hnRNPA1 knockdown decreased the anti-apoptotic protein Survivin. Significantly, Quercetin decreased hnRNPA1 in vivo and enhanced the effects of BET inhibitors at suppressing tumor growth. Together, these results demonstrate that Quercetin enhances the efficacy of BET inhibitors by suppressing hnRNPA1, and identify combination therapy with Quercetin and BET inhibitors for the treatment of cancer patients.
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Clarke, Joseph-Patrick W. E., Patricia A. Thibault, Hannah E. Salapa, David E. Kim, Catherine Hutchinson, and Michael C. Levin. "Multiple Sclerosis-Associated hnRNPA1 Mutations Alter hnRNPA1 Dynamics and Influence Stress Granule Formation." International Journal of Molecular Sciences 22, no. 6 (March 12, 2021): 2909. http://dx.doi.org/10.3390/ijms22062909.
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Evidence indicates that dysfunctional heterogeneous ribonucleoprotein A1 (hnRNPA1; A1) contributes to the pathogenesis of neurodegeneration in multiple sclerosis. Understanding molecular mechanisms of neurodegeneration in multiple sclerosis may result in novel therapies that attenuate neurodegeneration, thereby improving the lives of MS patients with multiple sclerosis. Using an in vitro, blue light induced, optogenetic protein expression system containing the optogene Cryptochrome 2 and a fluorescent mCherry reporter, we examined the effects of multiple sclerosis-associated somatic A1 mutations (P275S and F281L) in A1 localization, cluster kinetics and stress granule formation in real-time. We show that A1 mutations caused cytoplasmic mislocalization, and significantly altered the kinetics of A1 cluster formation/dissociation, and the quantity and size of clusters. A1 mutations also caused stress granule formation to occur more quickly and frequently in response to blue light stimulation. This study establishes a live cell optogenetics imaging system to probe localization and association characteristics of A1. It also demonstrates that somatic mutations in A1 alter its function and promote stress granule formation, which supports the hypothesis that A1 dysfunction may exacerbate neurodegeneration in multiple sclerosis.
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Ghosh, Meenakshi, and Mahavir Singh. "Structure specific recognition of telomeric repeats containing RNA by the RGG-box of hnRNPA1." Nucleic Acids Research 48, no. 8 (March 4, 2020): 4492–506. http://dx.doi.org/10.1093/nar/gkaa134.
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Abstract The telomere repeats containing RNA (TERRA) is transcribed from the C-rich strand of telomere DNA and comprises of UUAGGG nucleotides repeats in humans. The TERRA RNA repeats can exist in single stranded, RNA-DNA hybrid and G-quadruplex forms in the cell. Interaction of TERRA RNA with hnRNPA1 has been proposed to play critical roles in maintenance of telomere DNA. hnRNPA1 contains an N-terminal UP1 domain followed by an RGG-box containing C-terminal region. RGG-motifs are emerging as key protein motifs that recognize the higher order nucleic acid structures as well as are known to promote liquid-liquid phase separation of proteins. In this study, we have shown that the RGG-box of hnRNPA1 specifically recognizes the TERRA RNA G-quadruplexes that have loops in their topology, whereas it does not interact with the single-stranded RNA. Our results show that the N-terminal UP1 domain in the presence of the RGG-box destabilizes the loop containing TERRA RNA G-quadruplex efficiently compared to the RNA G-quadruplex that lacks loops, suggesting that unfolding of G-quadruplex structures by UP1 is structure dependent. Furthermore, we have compared the telomere DNA and TERRA RNA G-quadruplex binding by the RGG-box of hnRNPA1 and discussed its implications in telomere DNA maintenance.
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Gilpin, Kathleen M., Lydia Chang, and Mervyn J. Monteiro. "ALS-linked mutations in ubiquilin-2 or hnRNPA1 reduce interaction between ubiquilin-2 and hnRNPA1." Human Molecular Genetics 24, no. 9 (January 23, 2015): 2565–77. http://dx.doi.org/10.1093/hmg/ddv020.
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Jang, Han Na, Sun Joon Moon, Kyeong Cheon Jung, Sang Wan Kim, Hyeyoon Kim, Dohyun Han, and Jung Hee Kim. "Mass Spectrometry-Based Proteomic Discovery of Prognostic Biomarkers in Adrenal Cortical Carcinoma." Cancers 13, no. 15 (August 2, 2021): 3890. http://dx.doi.org/10.3390/cancers13153890.
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Adrenal cortical carcinoma (ACC) is an extremely rare disease with a variable prognosis. Current prognostic markers have limitations in identifying patients with a poor prognosis. Herein, we aimed to investigate the prognostic protein biomarkers of ACC using mass-spectrometry-based proteomics. We performed the liquid chromatography–tandem mass spectrometry (LC–MS/MS) using formalin-fixed paraffin-embedded (FFPE) tissues of 45 adrenal tumors. Then, we selected 117 differentially expressed proteins (DEPs) among tumors with different stages using the machine learning algorithm. Next, we conducted a survival analysis to assess whether the levels of DEPs were related to survival. Among 117 DEPs, HNRNPA1, C8A, CHMP6, LTBP4, SPR, NCEH1, MRPS23, POLDIP2, and WBSCR16 were significantly correlated with the survival of ACC. In age- and stage-adjusted Cox proportional hazard regression models, only HNRNPA1, LTBP4, MRPS23, POLDIP2, and WBSCR16 expression remained significant. These five proteins were also validated in TCGA data as the prognostic biomarkers. In this study, we found that HNRNPA1, LTBP4, MRPS23, POLDIP2, and WBSCR16 were protein biomarkers for predicting the prognosis of ACC.
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Ferreon, Allan Chris M., My D. Quan, Shih-Chu Liao, Phoebe Tsoi, and Josephine C. Ferreon. "Morphological evolution of hnRNPA1 pathological condensates." Biophysical Journal 121, no. 3 (February 2022): 357a. http://dx.doi.org/10.1016/j.bpj.2021.11.973.
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Kim, Hong Joo, Nam Chul Kim, Yong-Dong Wang, Emily A. Scarborough, Jennifer Moore, Zamia Diaz, Kyle S. MacLea, et al. "Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS." Nature 495, no. 7442 (March 2013): 467–73. http://dx.doi.org/10.1038/nature11922.
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Liao, Xin, Wei Zhan, Rui Li, Tian Tian, Lei Yu, and Qin Yang. "Irisin ameliorates endoplasmic reticulum stress and liver fibrosis through inhibiting PERK-mediated destabilization of HNRNPA1 in hepatic stellate cells." Biological Chemistry 402, no. 6 (January 20, 2021): 703–15. http://dx.doi.org/10.1515/hsz-2020-0251.
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Abstract Liver fibrosis is a common consequence of chronic liver diseases involved with the activation of hepatic stellate cells (HSCs) and endoplasmic reticulum (ER) stress. Irisin is a small polypeptide hormone that shows beneficial effects on metabolic disorders. The current study aimed to investigate the biological function of irisin on hepatic fibrosis. A mouse model of carbon tetrachloride (CCl4)-induced hepatic fibrosis was established. CCl4-treated mice showed elevated serum levels of AST and ALT, increased collagen accumulation, induced ER stress, and upregulated expressions of pro-fibrotic proteins in the liver compared to the controls. The administration of irisin, however, ameliorated CCl4-induced hepatic fibrosis in both cultured HSCs and mice. PKR-like ER kinase (PERK) is a key component of the ER stress-associated signaling pathway. We found that irisin treatment improved the stability of heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) via regulating the phosphorylation of PERK in mouse livers and isolated HSCs. Also, the knockdown of HNRNPA1 eliminated the hepatoprotective effects of irisin on hepatic fibrosis and ER stress. In summary, this study showed that irisin alleviated ER stress and hepatic fibrosis by inhibiting PERK-mediated HNRNPA1 destabilization, suggesting that irisin may represent a promising therapeutic strategy for patients with liver fibrosis.
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Martin, Erik W., F. Emil Thomasen, Nicole M. Milkovic, Matthew J. Cuneo, Christy R. Grace, Amanda Nourse, Kresten Lindorff-Larsen, and Tanja Mittag. "Interplay of folded domains and the disordered low-complexity domain in mediating hnRNPA1 phase separation." Nucleic Acids Research 49, no. 5 (February 12, 2021): 2931–45. http://dx.doi.org/10.1093/nar/gkab063.
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Abstract Liquid–liquid phase separation underlies the membrane-less compartmentalization of cells. Intrinsically disordered low-complexity domains (LCDs) often mediate phase separation, but how their phase behavior is modulated by folded domains is incompletely understood. Here, we interrogate the interplay between folded and disordered domains of the RNA-binding protein hnRNPA1. The LCD of hnRNPA1 is sufficient for mediating phase separation in vitro. However, we show that the folded RRM domains and a folded solubility-tag modify the phase behavior, even in the absence of RNA. Notably, the presence of the folded domains reverses the salt dependence of the driving force for phase separation relative to the LCD alone. Small-angle X-ray scattering experiments and coarse-grained MD simulations show that the LCD interacts transiently with the RRMs and/or the solubility-tag in a salt-sensitive manner, providing a mechanistic explanation for the observed salt-dependent phase separation. These data point to two effects from the folded domains: (i) electrostatically-mediated interactions that compact hnRNPA1 and contribute to phase separation and (ii) increased solubility at higher ionic strengths mediated by the folded domains. The interplay between disordered and folded domains can modify the dependence of phase behavior on solution conditions and can obscure signatures of physicochemical interactions underlying phase separation.
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Shi, Yijiang, Joseph Gera, and Alan Lichtenstein. "Interleukin-6 (IL-6) Enhances C-MYC Translation IN MULTIPLE MYELOMA (MM) CELLS: ROLE of IL-6-INDUCED EFFECTS On the C-MYC RNA-Binding PROTEIN, HNRNPA1." Blood 114, no. 22 (November 20, 2009): 3839. http://dx.doi.org/10.1182/blood.v114.22.3839.3839.
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Abstract Abstract 3839 Poster Board III-775 Our previous work (Cancer Research 68:10215, 2008) demonstrated that IL-6 enhanced c-myc protein expression in MM cells and function of the RNA-binding protein, hnRNPA1 (A1), was required. This occurred by way of enhanced cap-independent translation mediated via the internal ribosome entry site (IRES) in the 5'UTR of the myc RNA. IRES-dependent translation is the fail safe mechanism for protein expression when cap-dependent translation is suppressed by mTOR inhibition (with curtailed RNA cap-ribosome binding) and is especially important when an mRNA leader is relatively long and highly structured, such that scanning ribosomes are unlikely to efficiently initiate translation. The IRES directly recruits the ribosome to within close proximity to the start codon, bypassing the need for cap binding and ribosome scanning. HNRNPA1 (A1) is a documented IRES trans-acting factor (ITAF) for the myc IRES, facilitating translation but how its effects are enhanced by IL-6 is unknown. HNRNPA1 is a shuttling protein which binds the myc RNA in the nucleus and transports it to the cytoplasm. Initial experiments demonstrated that IL-6 stimulation of ANBL-6 and OCI-My5 MM cell lines, as well as several primary MM specimens, significantly increased the cytoplasmic localization of A1. To test if this enhanced cytoplasmic localization was critical, we stably expressed a dominant negative (DN) A1 gene that is incapable of nuclear-to-cytoplasmic shuttling and which also prevents endogenous hnRNPA1 shuttling. The DN also prevented A1-mediated transport of the shuttling protein, FUS. Expression of the DN in ANBL-6 cells prevented IL-6-induced effects on myc expression and on ANBL-6 cell growth. We also tested if IL-6 treatment affected A1 binding to the myc RNA by immunoprecipitating A1 and performing real time PCR on the immunoprecipitate for myc RNA levels. A significant increase in A1-myc RNA binding was confirmed. Mass spectroscopy demonstrated that IL-6 induced phosphorylation of A1 in its RNA-binding domain, which possibly mediated the enhanced binding. These results demonstrate that, by enhanced binding of the myc ITAF, hnRNPA1, to the myc IRES, and by enhanced transport of the complex to the translationally active cytoplasmic subcellular site, IL-6 may stimulate c-myc translation and subsequent MM cell growth. Disclosures: No relevant conflicts of interest to declare.
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Cao, Yun, Wei Zhang, Yi-Ting Jin, and Qiang Zou. "Mining the Prognostic Value of HNRNPAB and Its Function in Breast Carcinoma." International Journal of Genomics 2020 (May 14, 2020): 1–17. http://dx.doi.org/10.1155/2020/3750673.
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Heterogeneous nuclear ribonucleoproteins (HNRNPs) are crucial members in the pathogenesis and progression of numerous cancers. However, the expression pattern and clinical significance of HNRNPs in breast carcinoma (BC) remain to be investigated. In the present study, bioinformatic analysis identified HNRNPAB as the only commonly upregulated HNRNP in BC. Elevated expression of HNRNPAB was positively associated with more aggressive diseases and poorer survival rates in BC. Pathway analysis revealed that HNRNPAB coexpressed genes were enriched in the pathway of G2/M phase transition, and the expression level of HNRNPAB was strongly correlated with those of CCNB1, CDK1, CDC25A, and CDC25C. Experiments in vitro demonstrated that HNRNPAB knockdown suppressed cell proliferation and blocked the G2/M phase transition in BC. Taken together, this study provides the initial evidence that HNRNPAB may be employed as an innovative therapeutic target as well as a prognostic biomarker in BC patients.
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Harley, Jasmine, and Rickie Patani. "Stress-Specific Spatiotemporal Responses of RNA-Binding Proteins in Human Stem Cell-Derived Motor Neurons." International Journal of Molecular Sciences 21, no. 21 (November 6, 2020): 8346. http://dx.doi.org/10.3390/ijms21218346.
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RNA-binding proteins (RBPs) have been shown to play a key role in the pathogenesis of a variety of neurodegenerative disorders. Amyotrophic lateral sclerosis (ALS) is an exemplar neurodegenerative disease characterised by rapid progression and relatively selective motor neuron loss. Nuclear-to-cytoplasmic mislocalisation and accumulation of RBPs have been identified as a pathological hallmark of the disease, yet the spatiotemporal responses of RBPs to different extrinsic stressors in human neurons remain incompletely understood. Here, we used healthy induced pluripotent stem cell (iPSC)-derived motor neurons to model how different types of cellular stress affect the nucleocytoplasmic localisation of key ALS-linked RBPs. We found that osmotic stress robustly induced nuclear loss of TDP-43, SPFQ, FUS, hnRNPA1 and hnRNPK, with characteristic changes in nucleocytoplasmic localisation in an RBP-dependent manner. Interestingly, we found that RBPs displayed stress-dependent characteristics, with unique responses to both heat and oxidative stress. Alongside nucleocytoplasmic protein distribution changes, we identified the formation of stress- and RBP-specific nuclear and cytoplasmic foci. Furthermore, the kinetics of nuclear relocalisation upon recovery from extrinsic stressors was also found to be both stress- and RBP-specific. Importantly, these experiments specifically highlight TDP-43 and FUS, two of the most recognised RBPs in ALS pathogenesis, as exhibiting delayed nuclear relocalisation following stress in healthy human motor neurons as compared to SFPQ, hnRNPA1 and hnRNPK. Notably, ALS-causing valosin containing protein (VCP) mutations did not disrupt the relocalisation dynamics of TDP-43 or FUS in human motor neurons following stress. An increased duration of TDP-43 and FUS within the cytoplasm after stress may render the environment more aggregation-prone, which may be poorly tolerated in the context of ALS and related neurodegenerative disorders. In summary, our study addresses stress-specific spatiotemporal responses of neurodegeneration-related RBPs in human motor neurons. The insights into the nucleocytoplasmic dynamics of RBPs provided here may be informative for future studies examining both disease mechanisms and therapeutic strategy.
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White, Theresa L., Matthew Gable, Ye Jin, and Penelope A. Morel. "Understanding the role of hnRNPA1 on T cell differentiation and function in the Gut." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 141.19. http://dx.doi.org/10.4049/jimmunol.204.supp.141.19.
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Abstract Regulatory T cells (Treg) play a critical role in preventing autoimmunity diseases and maintaining tolerance in various tissues, particularly the gut. Peripheral derived Tregs (pTregs) are especially crucial in gut homeostasis and tolerance to commensal and food antigens. We have previously shown that knockdown of the RNA-binding protein, heterogeneous nuclear ribonucleoprotein (hnRNP) A1, reduces in vitro pTreg induction upon low TCR stimulation. In addition, we have shown that, under conditions of low TCR stimulation, in which pTreg are induced, hnRNP A1 is phosphorylated by Akt. In order to explore the impact of hnRNP A1 phosphorylation by Akt on pTreg induction in vivo we have generated a mutant mouse model, hnRNPA1-S199 in which the known Akt phosphorylation site on hnRNP A1 is mutated to Alanine. Extensive characterization of immune cells in this mutant mouse revealed no abnormalities in the number or frequency of major immune cell types at steady state. However, we identified abnormalities in the number of Treg in the mesenteric lymph nodes (mLN) in mutant mice, prompting further investigation. Using the Cytex Aurora flow cytometer we developed a 19 color T cell panel to characterize T cells in the mLN, Peyer’s patches and lamina propria. Detailed characterization of the pTreg and tTreg populations in the gut of WT and mutant mice will determine whether the abnormalities observed in the mLN are reflected in different intestinal areas. In addition, we are examining the induction of pTreg using an adoptive transfer model of OT-II TCR transgenic mutant and WT CD4 T cells followed by oral OVA administration. Further studies will focus on the mechanisms by which hnRNP A1 impacts pTreg induction.
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Nguyen, Doan C., Celia Saney, Ariel Ley, Iñaki Sanz, and F. Eun-Hyung Lee. "Human plasma cells switch on and turn off antibody secretion." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 123.20. http://dx.doi.org/10.4049/jimmunol.202.supp.123.20.
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Abstract Long-lived plasma cells (LLPC) are terminally-differentiated, non-dividing cells that reside in a protected and supportive bone marrow (BM) microenvironment. After terminal differentiation, antibody (Ab)-secreting cells (ASC) or plasma cells (PC) are believed to constitutively secrete Ab for a life-time. Recently, by integrated bioinformatics and using a novel in vitro cell-free BM microniche system, we demonstrated that protein factors such as fibronectin, YWHAZ, GAPDH, HSPD1, and hnRNPA1 are required for human ASC/PC survival. Specific blockade or inhibition of GAPDH, HSPD1, or hnRNPA1 resulted in loss of human ASC/PC IgG ELISpot frequencies. To understand whether ASC/PC secretion or survival was affected, we sequentially removed the inhibitors and replated the previously-treated ASC/PC in fresh conditions. Upon removal of the inhibitors, the inhibitory effects of Ab secretion were reversed, suggesting a functional recovery of Ab secretion of the inhibited ASC/PC. No evidence of additional ASC/PC proliferation was observed by BrdU uptake. Given the physiological functions of GAPDH, HSPD1, and hnRNPA1, it appeared that mechanisms involved in glucose or mitochondrial metabolism, or protein synthesis, can modulate Ab secretion of human ASC/PC. Together, these data suggest that human ASC/PC do not produce Ab constitutively, but can actually modulate Ab secretion based on their local microenvironment. Moreover, Ab secretion is not linked to survival. In essence, human ASC/PC switch on or turn off Ab secretion, but the exact mechanisms require further validation.
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Hackman, Peter, Salla M. Rusanen, Mridul Johari, Anna Vihola, Per Harald Jonson, Jaakko Sarparanta, Kati Donner, et al. "Dominant Distal Myopathy 3 (MPD3) Caused by a Deletion in the HNRNPA1 Gene." Neurology Genetics 7, no. 6 (October 27, 2021): e632. http://dx.doi.org/10.1212/nxg.0000000000000632.
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Background and ObjectivesTo determine the genetic cause of the disease in the previously reported family with adult-onset autosomal dominant distal myopathy (myopathy, distal, 3; MPD3).MethodsContinued clinical evaluation including muscle MRI and muscle pathology. A linkage analysis with single nucleotide polymorphism arrays and genome sequencing were used to identify the genetic defect, which was verified by Sanger sequencing. RNA sequencing was used to investigate the transcriptional effects of the identified genetic defect.ResultsSmall hand muscles (intrinsic, thenar, and hypothenar) were first involved with spread to the lower legs and later proximal muscles. Dystrophic changes with rimmed vacuoles and cytoplasmic inclusions were observed in muscle biopsies at advanced stage. A single nucleotide polymorphism array confirmed the previous microsatellite-based linkage to 8p22-q11 and 12q13-q22. Genome sequencing of three affected family members combined with structural variant calling revealed a small heterozygous deletion of 160 base pairs spanning the second last exon 10 of the heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) gene, which is in the linked region on chromosome 12. Segregation of the mutation with the disease was confirmed by Sanger sequencing. RNA sequencing showed that the mutant allele produces a shorter mutant mRNA transcript compared with the wild-type allele. Immunofluorescence studies on muscle biopsies revealed small p62 and larger TDP-43 inclusions.DiscussionA small exon 10 deletion in the gene HNRNPA1 was identified as the cause of MPD3 in this family. The new HNRNPA1-related phenotype, upper limb presenting distal myopathy, was thus confirmed, and the family displays the complexities of gene identification.
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Vuerich, Marta, Rasika Harshe, Anyan Xie, Luiza Abrahão-Frank, Barbora Gromova, Haohai Zhang, Samiran Mukherjee, et al. "Endogenous antisense regulates CD39 in Crohn’s disease upon interaction with nucleolin and heterogeneous-nuclear-ribonucleoprotein-A1." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 237.12. http://dx.doi.org/10.4049/jimmunol.204.supp.237.12.
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Abstract The ectoenzyme CD39 hydrolyzes ATP to generate immunosuppressive adenosine. We have shown that CD39 levels and activity are reduced in Treg and Th17-cells from Crohn’s patients. This impairment is linked to heightened levels of endogenous antisense (AS) present at the 3′ end of the human CD39 gene and regulating CD39 at mRNA and protein level. Here we note that CD39-specific AS is predominantly located in the nucleus of peripheral blood-derived Treg and Th17-cells of healthy subjects (HS) and Crohn’s disease patients. RNA pulldown assay followed by mass spectrometry shows that AS regulates CD39 upon interaction with nucleolin (NUCL) and heterogenous-nuclear-ribonucleoprotein-A1 (HNRNPA1). Silencing of NUCL and/or HNRNPA1 results in higher CD39 levels in both Treg and Th17-cells. Blockade of antisense in vitro using FANA oligonucleotides decreases AS while boosting CD39 in HS and Crohn’s Treg and Th17-cells. AS silencing in vivo ameliorates experimental colitis induced by trinitrobenzene-sulfonic-acid in NOD/scid/gamma mice reconstituted with antisense+ human CD4-cells and concomitantly administered FANA oligonucleotides. Compared to untreated controls, FANA-treated mice show decreased disease activity index, higher colon length, lower histology score and, phenotypically, increased proportions of circulating CD39+CD4+-cells and decreased frequencies of peripheral blood and splenic CD4+IL-17+-cells. In conclusion, CD39-specific AS dampens CD39 levels in Crohn’s Treg and Th17-cells by interacting with NUCL and HNRNPA1. Inhibition of AS controls disease activity in experimental colitis suggesting that AS blockade might serve as a novel therapeutic tool to restore CD39 and curb inflammation in Crohn’s disease.
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Le Ber, Isabelle, Inge Van Bortel, Gael Nicolas, Kawtar Bouya-Ahmed, Agnès Camuzat, David Wallon, Anne De Septenville, et al. "hnRNPA2B1 and hnRNPA1 mutations are rare in patients with “multisystem proteinopathy” and frontotemporal lobar degeneration phenotypes." Neurobiology of Aging 35, no. 4 (April 2014): 934.e5–934.e6. http://dx.doi.org/10.1016/j.neurobiolaging.2013.09.016.
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Liu, Xiao, Takumi Ishizuka, Hong-Liang Bao, Kei Wada, Yuma Takeda, Keisuke Iida, Kazuo Nagasawa, Danzhou Yang, and Yan Xu. "Structure-Dependent Binding of hnRNPA1 to Telomere RNA." Journal of the American Chemical Society 139, no. 22 (May 24, 2017): 7533–39. http://dx.doi.org/10.1021/jacs.7b01599.
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Roy, Rajat, Yueyang Huang, Michael J. Seckl, and Olivier E. Pardo. "Emerging roles of hnRNPA1 in modulating malignant transformation." Wiley Interdisciplinary Reviews: RNA 8, no. 6 (August 8, 2017): e1431. http://dx.doi.org/10.1002/wrna.1431.
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Sgobbi de Souza, Paulo Victor, Bruno de Mattos Lombardi Badia, Eduardo Augusto Gonçalves, Igor Braga Farias, Wladimir Bocca Vieira de Rezende Pinto, and Acary Souza Bulle Oliveira. "Hereditary inclusion body myopathy: a clinical and genetic review." Revista Neurociências 28 (July 24, 2020): 1–23. http://dx.doi.org/10.34024/rnc.2020.v28.10569.
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Introduction. Inclusion body myositis represents the most common acquired myopathy in clinical practice in patients over 50 years old. Despite classical approach to this myopathy as an inflammatory disorder, a muscle degenerative disorder is now considered the main mechanism linked to these vacuolar myopathies. Hereditary presentations, although quite rare, represent an expanding and underrecognized group in clinical practice. Objective. perform a structured review of the current literature regarding hereditary inclusion body myopathies. Method. review of U.S. NLM PubMed and MEDLINE database of original articles, case reports, case series and review articles including the terms “inclusion body myositis” OR “inclusion body myopathy” AND “genetics” OR “hereditary”. Results. We present in this article a wide review regarding the main clinical, imaging, pathophysiological, genetic and therapeutic aspects related to hereditary myopathies linked to seven different clinical and genetic presentations (GNE, MATR3, VCP, SQSTM1, MYH2, HNRNPA2B1 and HNRNPA1). Conclusion. Hereditary inclusion body myopathy is associated with at least 7 distinct clinic and genetic monogenic forms.
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Zhang, Chao, Xiaolin Ji, Zhenguang Chen, and Zhichao Yao. "Asiaticoside Suppresses Gastric Cancer Progression and Induces Endoplasmic Reticulum Stress through the miR-635/HMGA1 Axis." Journal of Immunology Research 2022 (June 2, 2022): 1–12. http://dx.doi.org/10.1155/2022/1917585.
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Objective. Gastric cancer is a prevalent malignant tumor with high morbidity and poor prognosis. Asiaticoside (AC) has antitumor effects, while its role in gastric cancer is elusive. Thus, this study investigated the effect of AC on gastric cancer progression. Methods. Cell viability and migration were determined using the CCK-8 and Transwell migration assay. Endoplasmic reticulum stress was detected through measuring the expressions of GRP78, Chop, and hnRNPA1 by Western blot. The luciferase assay confirmed the relationship between miR-635 and High Mobility Group AT-Hook 1 (HMGA1). The effect of AC on tumor growth was evaluated by establishing a xenograft tumor. The survival rate of mice was analyzed by Kaplan-Meier analysis. Results. AC suppressed gastric cancer cell viability and restrained cell migration. AC inhibited the expressions of the cell proliferation marker PCNA and EMT-related marker N-cadherin and increased E-cadherin expression. AC elevated the levels of GRP78 and Chop and suppressed the level of hnRNPA1. In addition, AC restrained gastric cancer proliferation and migration ability and induced endoplasmic reticulum stress by upregulating miR-635 expression. Furthermore, HMGA1 was proven to be a target of miR-635. AC constrained gastric cancer cell proliferation and migration and promoted endoplasmic reticulum stress by regulating HMGA1. Moreover, AC suppressed in vivo tumor growth and improved the survival time of mice. Additionally, AC elevated the expressions of miR-635, E-cadherin, GRP78, and Chop and inhibited Ki-67, HMGA1, N-cadherin, and hnRNPA1 expressions in tumor tissues of mice. Conclusion. AC suppressed gastric cancer progression and induced endoplasmic reticulum stress via the miR-635/HMGA1 axis, providing a valuable drug against gastric cancer.
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Harrison, Alice Ford, and James Shorter. "RNA-binding proteins with prion-like domains in health and disease." Biochemical Journal 474, no. 8 (April 7, 2017): 1417–38. http://dx.doi.org/10.1042/bcj20160499.
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Approximately 70 human RNA-binding proteins (RBPs) contain a prion-like domain (PrLD). PrLDs are low-complexity domains that possess a similar amino acid composition to prion domains in yeast, which enable several proteins, including Sup35 and Rnq1, to form infectious conformers, termed prions. In humans, PrLDs contribute to RBP function and enable RBPs to undergo liquid–liquid phase transitions that underlie the biogenesis of various membraneless organelles. However, this activity appears to render RBPs prone to misfolding and aggregation connected to neurodegenerative disease. Indeed, numerous RBPs with PrLDs, including TDP-43 (transactivation response element DNA-binding protein 43), FUS (fused in sarcoma), TAF15 (TATA-binding protein-associated factor 15), EWSR1 (Ewing sarcoma breakpoint region 1), and heterogeneous nuclear ribonucleoproteins A1 and A2 (hnRNPA1 and hnRNPA2), have now been connected via pathology and genetics to the etiology of several neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal dementia, and multisystem proteinopathy. Here, we review the physiological and pathological roles of the most prominent RBPs with PrLDs. We also highlight the potential of protein disaggregases, including Hsp104, as a therapeutic strategy to combat the aberrant phase transitions of RBPs with PrLDs that likely underpin neurodegeneration.
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Mascarenhas, Joseph B., Alex Y. Tchourbanov, Sergei M. Danilov, Tong Zhou, Ting Wang, and Joe G. N. Garcia. "The Splicing Factor hnRNPA1 Regulates Alternate Splicing of theMYLKGene." American Journal of Respiratory Cell and Molecular Biology 58, no. 5 (May 2018): 604–13. http://dx.doi.org/10.1165/rcmb.2017-0141oc.
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Chen, C., L. Yuming, L. Hao, H. Wang, and L. Tianxin. "Exosomal hnRNPA1 promotes the lymphatic metastasis of bladder cancer." European Urology Open Science 19 (July 2020): e423. http://dx.doi.org/10.1016/s2666-1683(20)32844-5.
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Travina, Aleksandra O., Nadya V. Ilicheva, Alexey G. Mittenberg, Sergey V. Shabelnikov, Anastasia V. Kotova, and Olga I. Podgornaya. "The Long Linker Region of Telomere-Binding Protein TRF2 Is Responsible for Interactions with Lamins." International Journal of Molecular Sciences 22, no. 7 (March 24, 2021): 3293. http://dx.doi.org/10.3390/ijms22073293.
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Telomere-binding factor 2 (TRF2) is part of the shelterin protein complex found at chromosome ends. Lamin A/C interacts with TRF2 and influences telomere position. TRF2 has an intrinsically disordered region between the ordered dimerization and DNA-binding domains. This domain is referred to as the long linker region of TRF2, or udTRF2. We suggest that udTRF2 might be involved in the interaction between TRF2 and lamins. The recombinant protein corresponding to the udTRF2 region along with polyclonal antibodies against this region were used in co-immunoprecipitation with purified lamina and nuclear extracts. Co-immunoprecipitation followed by Western blots and mass spectrometry indicated that udTRF2 interacts with lamins, preferably lamins A/C. The interaction did not involve any lamin-associated proteins, was not dependent on the post-translation modification of lamins, nor did it require their higher-order assembly. Besides lamins, a number of other udTRF2-interacting proteins were identified by mass spectrometry, including several heterogeneous nuclear ribonucleoproteins (hnRNP A2/B1, hnRNPA1, hnRNP A3, hnRNP K, hnRNP L, hnRNP M), splicing factors (SFPQ, NONO, SRSF1, and others), helicases (DDX5, DHX9, and Eif4a3l1), topoisomerase I, and heat shock protein 71, amongst others. Some of the identified interactors are known to be involved in telomere biology; the roles of the others remain to be investigated. Thus, the long linker region of TRF2 (udTRF2) is a regulatory domain responsible for the association between TRF2 and lamins and is involved in interactions with other proteins.