Journal articles: 'IFI16'

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Fujiuchi, Nobuko, Jason A. Aglipay, Takao Ohtsuka, Naoki Maehara, Fikret Sahin, Gloria H. Su, Sam W. Lee, and Toru Ouchi. "Requirement of IFI16 for the Maximal Activation of p53 Induced by Ionizing Radiation." Journal of Biological Chemistry 279, no. 19 (February 27, 2004): 20339–44. http://dx.doi.org/10.1074/jbc.m400344200.

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IFI16 is a member of the PYRIN superfamily that has been implicated in BRCA1-mediated apoptosis and inflammation signaling pathways. Here we report that most breast cancer cell lines examined expressed decreased mRNA and protein levels of IFI16, although IFI16 is expressed in human primary normal mammary epithelial cells. Significantly, immunohistochemical analysis of tissues from 25 breast cancer patients demonstrated that carcinoma cells showed negative or weaker staining of IFI16 compared with positive nuclear staining in normal mammary duct epithelium. si-RNA-mediated reduction of IFI16 resulted in perturbation of p53 activation when treated with ionizing radiation (IR). Expression of IFI16 enhanced p53 transcriptional activity in cells exposed to IR. Adenovirus expression of IFI16 in IFI16-deficient MCF7 induced apoptosis, which was enhanced by radiomimetic neocarcinostatin treatment. Tetracycline-regulated IFI16 also induced apoptosis when coexpressed with p53 in p53-deficient EJ cells subjected to IR, suggesting that IFI16 is involved in p53-mediated transmission of apoptosis signaling. Consistent with these results, expression of IFI16 enhanced activation of the known p53 target genes, includingp21, Hdm2, andbaxin MCF7 cells. These results suggest that loss of IFI16 results in deregulation of p53-mediated apoptosis, leading to cancer development.

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Alunno, A., V. Caneparo, F. Carubbi, O. Bistoni, S. Caterbi, M. Gariglio, E. Bartoloni, S. Landolfo, and R. Gerli. "Interferon gamma-inducible protein 16 (IFI16) and anti-IFI16 antibodies in primary Sjögren’s syndrome: findings in serum and minor salivary glands." Reumatismo 67, no. 3 (February 9, 2016): 85. http://dx.doi.org/10.4081/reumatismo.2015.839.

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The interferon (IFN) signature, namely the overexpression of IFN-inducible genes is a crucial aspect in the pathogenesis of primary Sjögren’s syndrome (pSS). The IFN-inducible IFI16 protein, normally expressed in cell nuclei, may be overexpressed, mislocalized in the cytoplasm and secreted in the extracellular milieu in several autoimmune disorders including pSS. This leads to tolerance breaking to this self-protein and development of anti-IFI16 antibodies. The aim of this study was to identify pathogenic and clinical significance of IFI16 and anti-IFI16 autoantibodies in pSS. IFI16 and anti-IFI16 were assessed in the serum of 30 pSS patients and one-hundred healthy donors (HD) by ELISA. IFI16 was also evaluated in 5 minor salivary glands (MSGs) of pSS patients and 5 MSGs of non-pSS patients with sicca symptoms by immunohistochemistry. Normal MSGs do not constitutively express IFI16. Conversely, in pSS-MSGs a marked expression and cytoplasmic mislocalization of IFI16 by epithelial cells was observed with infiltrations in lymphocytes and peri/ intra-lesional endothelium. pSS patients display higher serum levels of both IFI16 and anti-IFI16 autoantibodies compared to HD. Our data suggest that IFI16 protein may be involved in the initiation and perpetuation of glandular inflammation occurring in pSS.

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Chang, Xiaobo, Xibao Shi, Xiaozhuan Zhang, Li Wang, Xuewu Li, Aiping Wang, Ruiguang Deng, Enmin Zhou, and Gaiping Zhang. "IFI16 Inhibits Porcine Reproductive and Respiratory Syndrome Virus 2 Replication in a MAVS-Dependent Manner in MARC-145 Cells." Viruses 11, no. 12 (December 16, 2019): 1160. http://dx.doi.org/10.3390/v11121160.

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Porcine reproductive and respiratory syndrome virus (PRRSV) is a single-stranded positive-sense RNA virus, and the current strategies for controlling PRRSV are limited. Interferon gamma-inducible protein 16 (IFI16) has been reported to have a broader role in the regulation of the type I interferons (IFNs) response to RNA and DNA viruses. However, the function of IFI16 in PRRSV infection is unclear. Here, we revealed that IFI16 acts as a novel antiviral protein against PRRSV-2. IFI16 could be induced by interferon-beta (IFN-β). Overexpression of IFI16 could significantly suppress PRRSV-2 replication, and silencing the expression of endogenous IFI16 by small interfering RNAs led to the promotion of PRRSV-2 replication in MARC-145 cells. Additionally, IFI16 could promote mitochondrial antiviral signaling protein (MAVS)-mediated production of type I interferon and interact with MAVS. More importantly, IFI16 exerted anti-PRRSV effects in a MAVS-dependent manner. In conclusion, our data demonstrated that IFI16 has an inhibitory effect on PRRSV-2, and these findings contribute to understanding the role of cellular proteins in regulating PRRSV replication and may have implications for the future antiviral strategies.

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Biolatti, Matteo, Valentina Dell'Oste, Sara Pautasso, Jens von Einem, Manfred Marschall, Bodo Plachter, Marisa Gariglio, Marco De Andrea, and Santo Landolfo. "Regulatory Interaction between the Cellular Restriction Factor IFI16 and Viral pp65 (pUL83) Modulates Viral Gene Expression and IFI16 Protein Stability." Journal of Virology 90, no. 18 (July 6, 2016): 8238–50. http://dx.doi.org/10.1128/jvi.00923-16.

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ABSTRACTA key player in the intrinsic resistance against human cytomegalovirus (HCMV) is the interferon-γ-inducible protein 16 (IFI16), which behaves as a viral DNA sensor in the first hours postinfection and as a repressor of viral gene transcription in the later stages. Previous studies on HCMV replication demonstrated that IFI16 binds to the viral protein kinase pUL97, undergoes phosphorylation, and relocalizes to the cytoplasm of infected cells. In this study, we demonstrate that the tegument protein pp65 (pUL83) recruits IFI16 to the promoter of the UL54 gene and downregulates viral replication, as shown by use of the HCMV mutant v65Stop, which lacks pp65 expression. Interestingly, at late time points of HCMV infection, IFI16 is stabilized by its interaction with pp65, which stood in contrast to IFI16 degradation, observed in herpes simplex virus 1 (HSV-1)-infected cells. Moreover, we found that its translocation to the cytoplasm, in addition to pUL97, strictly depends on pp65, as demonstrated with the HCMV mutant RV-VM1, which expresses a form of pp65 unable to translocate into the cytoplasm. Thus, these data reveal a dual role for pp65: during early infection, it modulates IFI16 activity at the promoter of immediate-early and early genes; subsequently, it delocalizes IFI16 from the nucleus into the cytoplasm, thereby stabilizing and protecting it from degradation. Overall, these data identify a novel activity of the pp65/IFI16 interactome involved in the regulation of UL54 gene expression and IFI16 stability during early and late phases of HCMV replication.IMPORTANCEThe DNA sensor IFI16, a member of the PYHIN proteins, restricts HCMV replication by impairing viral DNA synthesis. Using a mutant virus lacking the tegument protein pp65 (v65Stop), we demonstrate that pp65 recruits IFI16 to the early UL54 gene promoter. As a putative counteraction to its restriction activity, pp65 supports the nucleocytoplasmic export of IFI16, which was demonstrated with the viral mutant RV-VM1 expressing a nuclearly retained pp65. These data reveal a dual role of pp65 in IFI16 regulation: in the early phase of HCMV infection, it contributes to viral evasion from IFI16 restriction activity, while at later time points, it promotes the nuclear delocalization of IFI16, thereby stabilizing and protecting it from degradation. In the present work, we further clarify the mechanisms HCMV relies on to overcome intracellular innate immune restriction and provide new insights into the relevance of DNA-sensing restriction factor IFI16 during HCMV infection.

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Caposio, Patrizia, Francesca Gugliesi, Claudia Zannetti, Simone Sponza, Michele Mondini, Enzo Medico, John Hiscott, et al. "A Novel Role of the Interferon-inducible Protein IFI16 as Inducer of Proinflammatory Molecules in Endothelial Cells." Journal of Biological Chemistry 282, no. 46 (August 14, 2007): 33515–29. http://dx.doi.org/10.1074/jbc.m701846200.

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The human IFI16 gene is an interferon-inducible gene implicated in the regulation of endothelial cell proliferation and tube morphogenesis. Immunohistochemical analysis has demonstrated that this gene is highly expressed in endothelial cells in addition to hematopoietic tissues. In this study, gene array analysis of human umbilical vein endothelial cells overexpressing IFI16 revealed an increased expression of genes involved in immunomodulation, cell growth, and apoptosis. Consistent with these observations, IFI16 triggered expression of adhesion molecules such as ICAM-1 and E-selectin or chemokines such as interleukin-8 or MCP-1. Treatment of cells with short hairpin RNA targeting IFI16 significantly inhibited ICAM-1 induction by interferon (IFN)-γ demonstrating that IFI16 is required for proinflammatory gene stimulation. Moreover, functional analysis of the ICAM-1 promoter by deletion- or site-specific mutation demonstrated that NF-κB is the main mediator of IFI16-driven gene induction. NF-κB activation appears to be triggered by IFI16 through a novel mechanism involving suppression of IκBα mRNA and protein expression. Support for this finding comes from the observation that IFI16 targeting with specific short hairpin RNA down-regulates NF-κB binding activity to its cognate DNA and inhibits ICAM-1 expression induced by IFN-γ. Using transient transfection and luciferase assay, electrophoretic mobility shift assay, and chromatin immunoprecipitation, we demonstrate indeed that activation of the NF-κB response is mediated by IFI16-induced block of Sp1-like factor recruitment to the promoter of the IκBα gene, encoding the main NF-κB inhibitor. Activation of NF-κB accompanied by induction of proinflammatory molecules was also observed when IκBα expression was down-regulated by specific small interfering RNA, resulting in an outcome similar to that observed with IFI16 overexpression. Taken together, these data implicate IFI16 as a novel regulator of endothelial proinflammatory activity and provide new insights into the physiological functions of the IFN-inducible gene IFI16.

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Xiao, Tsan, and Tengchuan Jin. "Ligand binding and signaling by IFI16 (INM8P.400)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 195.8. http://dx.doi.org/10.4049/jimmunol.194.supp.195.8.

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Abstract IFI16 plays important roles in inflammatory immune responses to viral infections as well as in autoimmune disorders such as lupus. It has been implicated in interferon induction through a STING-mediated pathway, as well as in inflammasome activation during recognition of viral DNA in the nucleus. Despite recent progress that highlighted the mechanisms of dsDNA binding by the IFI16 HINb domain, there are major gaps in our understanding of the ligand-induced structural changes, the polymerization of IFI16 mediated by dsDNA and its PYD domain, its interaction with downstream signaling partners, the regulation of IFI16 by host and microbe-derived molecules, and the cell-type specific immune responses mediated by IFI16. We have characterized the key structural determinants in both the recognition of dsDNA by IFI16 and the potential downstream signaling events. We will outline the implications of our findings and discuss future directions in clarifying the structure and function of IFI16 in infectious diseases and autoimmune disorders.

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Orzalli, Megan H., Nicole M. Broekema, and David M. Knipe. "Relative Contributions of Herpes Simplex Virus 1 ICP0 and vhs to Loss of Cellular IFI16 Vary in Different Human Cell Types." Journal of Virology 90, no. 18 (July 13, 2016): 8351–59. http://dx.doi.org/10.1128/jvi.00939-16.

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ABSTRACTThe herpes simplex virus 1 (HSV-1) ICP0 protein is an E3 ubiquitin ligase that promotes the degradation of several host cell proteins. Most studies have found that ICP0 promotes the loss of IFI16 in infected cells, but one study reported that ICP0 was not necessary or sufficient for loss of IFI16 in a tumor-derived cell line. Therefore, in this study, we examined the requirement for ICP0 in promoting the loss of IFI16 in several normal and tumor-derived cell lines. HSV-1 infection resulted in an observable decrease of IFI16 protein levels in normal human foreskin fibroblasts (HFFs), normal oral keratinocytes (NOKs), and HeLa cells but not in U2OS cells. During infection with an ICP0-null virus, we observed a reduced loss of IFI16 in HFFs and NOKs but not in HeLa cells. Ectopic expression of ICP0 from a transfected plasmid was sufficient to promote the loss of IFI16 in HFFs and NOKs. In the absence of ICP0, we observed a delayed reduction of IFI16 protein that correlated with a reduction in the steady-state levels ofIFI16mRNA. In addition, we show that the ICP0-independent loss of IFI16 in HeLa cells is dependent in part on the activity of the viral virion host shutoff (vhs) tegument protein. Together, these results demonstrate that HSV-1 promotes the loss of IFI16 through at least two mechanisms: (i) by ICP0-dependent degradation of IFI16 and (ii) by vhs-dependent turnover ofIFI16mRNA. In addition, this study highlights a potential intrinsic difference between normal and tumor-derived cells for the activities of IFI16 and HSV-1 ICP0.IMPORTANCEHSV-1 is a ubiquitous virus that establishes a lifetime persistent infection in humans. The relative success of HSV-1 as a pathogen is, in part, dependent on the expression of viral proteins that counteract host intrinsic defense mechanisms and that modulate immune responses during viral infection. In this study, we examined the relative roles of two viral gene products for the ability to promote loss of the antiviral IFI16 DNA sensor. We demonstrate that the viral immediate early ICP0 protein plays a dominant role in the loss of IFI16 in normal, but not tumor-derived, human cell lines. In contrast, viral vhs-mediated loss of IFI16 by mRNA destabilization is revealed to be dominant in tumor-derived cells in which ICP0 is nonfunctional. Together, these results contribute to our understanding of how HSV-1 modulates IFI16 protein levels and highlight cell-type-dependent differences between normal and tumor-derived cells.

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De Andrea, M., M. De Santis, V. Caneparo, E. Generali, S. Sirotti, N. Isailovic, G. M. Guidelli, et al. "Serum IFI16 and anti‐IFI16 antibodies in psoriatic arthritis." Clinical & Experimental Immunology 199, no. 1 (October 15, 2019): 88–96. http://dx.doi.org/10.1111/cei.13376.

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Yamauchi, Moriyasu, Takafumi Nakano, Torahiko Nakashima, Ryuji Yasumatsu, Kazuki Hashimoto, Satoshi Toh, Hideki Shiratsuchi, Yoshinao Oda, and Shizuo Komune. "Interferon Inducible IFI16 Expression in p16 Positive Squamous Cell Carcinoma of the Oropharynx." ISRN Otolaryngology 2013 (July 11, 2013): 1–7. http://dx.doi.org/10.1155/2013/263271.

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Human-papillomavirus- (HPV-) positive oropharyngeal squamous cell carcinomas (OPSCC) are reported to be more responsive to treatment and to be related to a favorable prognosis compared with non-HPV carcinomas. However, the molecular basis of the responsiveness is unclear. Interferon inducible IFI16, which is implicated in the control of cell growth, apoptosis, angiogenesis, and immunomodulation in various types of cancers, is reported to be frequently expressed in the HPV-positive head and neck SCC and to correlate with a better prognosis. In this study, we hypothesized that HPV related OPSCC expresses IFI16 resulting in favorable prognosis. To clarify the relationship between the prognosis of HPV related OPSCC patients and IFI16 status, we examined immunohistologically the pretreatment specimens of OPSCC for the expression of p16 as a surrogate marker of HPV infection and IFI16. We could not show that the expression of IFI16 is associated with that of p16. There was no significant difference in the survival rate between IFI16 positive and negative groups. Patients with p16 negative tumor exhibited worse survival rate regardless of IFI16 status. In this limited case series, we could not conclude that IFI16 expression is altered in p16 positive OPSCC and that it would be a new predictive marker or a useful therapeutic tool.

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Roy, Arunava, Dipanjan Dutta, Jawed Iqbal, Gina Pisano, Olsi Gjyshi, Mairaj Ahmed Ansari, Binod Kumar, and Bala Chandran. "Nuclear Innate Immune DNA Sensor IFI16 Is Degraded during Lytic Reactivation of Kaposi's Sarcoma-Associated Herpesvirus (KSHV): Role of IFI16 in Maintenance of KSHV Latency." Journal of Virology 90, no. 19 (July 27, 2016): 8822–41. http://dx.doi.org/10.1128/jvi.01003-16.

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ABSTRACTIFI16 (interferon gamma-inducible protein 16) recognizes nuclear episomal herpesvirus (Kaposi's sarcoma-associated herpesvirus [KSHV], Epstein-Barr virus [EBV], and herpes simplex virus 1 [HSV-1]) genomes and induces the inflammasome and interferon beta responses. It also acts as a lytic replication restriction factor and inhibits viral DNA replication (human cytomegalovirus [HCMV] and human papillomavirus [HPV]) and transcription (HSV-1, HCMV, and HPV) through epigenetic modifications of the viral genomes. To date, the role of IFI16 in the biology of latent viruses is not known. Here, we demonstrate that knockdown of IFI16 in the latently KSHV-infected B-lymphoma BCBL-1 and BC-3 cell lines results in lytic reactivation and increases in levels of KSHV lytic transcripts, proteins, and viral genome replication. Similar results were also observed during KSHV lytic cycle induction in TREX-BCBL-1 cells with the doxycycline-inducible lytic cycle switch replication and transcription activator (RTA) gene. Overexpression of IFI16 reduced lytic gene induction by the chemical agent 12-O-tetradecoylphorbol-13-acetate (TPA). IFI16 protein levels were significantly reduced or absent in TPA- or doxycycline-induced cells expressing lytic KSHV proteins. IFI16 is polyubiquitinated and degraded via the proteasomal pathway. The degradation of IFI16 was absent in phosphonoacetic acid-treated cells, which blocks KSHV DNA replication and, consequently, late lytic gene expression. Chromatin immunoprecipitation assays of BCBL-1 and BC-3 cells demonstrated that IFI16 binds to KSHV gene promoters. Uninfected epithelial SLK and osteosarcoma U2OS cells transfected with KSHV luciferase promoter constructs confirmed that IFI16 functions as a transcriptional repressor. These results reveal that KSHV utilizes the innate immune nuclear DNA sensor IFI16 to maintain its latency and repression of lytic transcripts, and a late lytic KSHV gene product(s) targets IFI16 for degradation during lytic reactivation.IMPORTANCELike all herpesviruses, latency is an integral part of the life cycle of Kaposi's sarcoma-associated herpesvirus (KSHV), an etiological agent for many human cancers. Herpesviruses utilize viral and host factors to successfully evade the host immune system to maintain latency. Reactivation is a complex event where the latent episomal viral genome springs back to active transcription of lytic cycle genes. Our studies reveal that KSHV has evolved to utilize the innate immune sensor IFI16 to keep lytic cycle transcription in dormancy. We demonstrate that IFI16 binds to the lytic gene promoter, acts as a transcriptional repressor, and thereby helps to maintain latency. We also discovered that during the late stage of lytic replication, KSHV selectively degrades IFI16, thus relieving transcriptional repression. This is the first report to demonstrate the role of IFI16 in latency maintenance of a herpesvirus, and further understanding will lead to the development of strategies to eliminate latent infection.

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Lo Cigno, Irene, Marco De Andrea, Cinzia Borgogna, Silvia Albertini, Manuela M. Landini, Alberto Peretti, Karen E. Johnson, Bala Chandran, Santo Landolfo, and Marisa Gariglio. "The Nuclear DNA Sensor IFI16 Acts as a Restriction Factor for Human Papillomavirus Replication through Epigenetic Modifications of the Viral Promoters." Journal of Virology 89, no. 15 (May 13, 2015): 7506–20. http://dx.doi.org/10.1128/jvi.00013-15.

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ABSTRACTThe human interferon-inducible IFI16 protein, an innate immune sensor of intracellular DNA, was recently demonstrated to act as a restriction factor for human cytomegalovirus (HCMV) and herpes simplex virus 1 (HSV-1) infection by inhibiting both viral-DNA replication and transcription. Through the use of two distinct cellular models, this study provides strong evidence in support of the notion that IFI16 can also restrict human papillomavirus 18 (HPV18) replication. In the first model, an immortalized keratinocyte cell line (NIKS) was used, in which the IFI16 protein was knocked down through the use of small interfering RNA (siRNA) technology and overexpressed following transduction with the adenovirus IFI16 (AdVIFI16) vector. The second model consisted of U2OS cells transfected by electroporation with HPV18 minicircles. In differentiated IFI16-silenced NIKS-HPV18 cells, viral-load values were significantly increased compared with differentiated control cells. Consistent with this, IFI16 overexpression severely impaired HPV18 replication in both NIKS and U2OS cells, thus confirming its antiviral restriction activity. In addition to the inhibition of viral replication, IFI16 was also able to reduce viral transcription, as demonstrated by viral-gene expression analysis in U2OS cells carrying episomal HPV18 minicircles and HeLa cells. We also provide evidence that IFI16 promotes the addition of heterochromatin marks and the reduction of euchromatin marks on viral chromatin at both early and late promoters, thus reducing both viral replication and transcription. Altogether, these results argue that IFI16 restricts chromatinized HPV DNA through epigenetic modifications and plays a broad surveillance role against viral DNA in the nucleus that is not restricted to herpesviruses.IMPORTANCEIntrinsic immunity is mediated by cellular restriction factors that are constitutively expressed and active even before a pathogen enters the cell. The host nuclear factor IFI16 acts as a sensor of foreign DNA and an antiviral restriction factor, as recently demonstrated by our group for human cytomegalovirus (HCMV) and herpes simplex virus 1 (HSV-1). Here, we provide the first evidence that IFI16 inhibits HPV18 replication by repressing viral-gene expression and replication. This antiviral restriction activity was observed in immortalized keratinocytes transfected with the religated genomes and in U2OS cells transfected with HPV18 minicircles, suggesting that it is not cell type specific. We also show that IFI16 promotes the assembly of heterochromatin on HPV DNA. These changes in viral chromatin structure lead to the generation of a repressive state at both early and late HPV18 promoters, thus implicating the protein in the epigenetic regulation of HPV gene expression and replication.

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Thompson, Mikayla, Soren Jensen, Shruti Sharma, Katherine Fitzgerald, and Evelyn Kurt-Jones. "The role of IFI16 in the innate immune response to cytosolic nucleic acids (P1395)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 57.9. http://dx.doi.org/10.4049/jimmunol.190.supp.57.9.

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Abstract Recently, the Interferon Gamma Inducible (IFI)16 was linked to cytoplasmic DNA induced type I interferon (IFN) responses. IFI16 was shown to associate with Stimulator of IFN genes (STING), leading to TANK binding kinase-1 (TBK1) dependent phosphorylation of interferon regulatory factor 3 (IRF3) and transcription of type I IFN genes. Here we created THP1 monocytic cell lines with stable knockdown of IFI16 by lentiviral transduction of shRNA and demonstrated that IFI16 knockdown leads to a severely attenuated type I IFN response following treatment of cells with either synthetic DNA ligands, or after infection with DNA viruses such as HSV-1. Surprisingly, these cells were also compromised in their ability to induce type I IFNs to other non-DNA ligands including synthetic 5’pppRNA and Sendai Virus, both of which signal via RIG-I. In contrast the NF-kB regulated cytokines IL-6 and IL-1β remain unaffected in IFI16 knockdown cells. Utilizing Nanostring technology, we also determined that IFI16 is capable of regulating DNA and RNA induced expression of a panel of Interferon Stimulated genes (ISGs), including RIG-I. We also monitored key steps in the type 1 IFN pathway and found that levels of total IRF3 were also reduced in IFI16 knockdown cells. These results suggest that IFI16 senses DNA viruses, eliciting a type I IFN response, but also acts more broadly in the regulation of ISGs in response to both DNA and RNA viruses.

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Orzalli, Megan H., Nicole M. Broekema, Benjamin A. Diner, Dustin C. Hancks, Nels C. Elde, Ileana M. Cristea, and David M. Knipe. "cGAS-mediated stabilization of IFI16 promotes innate signaling during herpes simplex virus infection." Proceedings of the National Academy of Sciences 112, no. 14 (March 23, 2015): E1773—E1781. http://dx.doi.org/10.1073/pnas.1424637112.

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Interferon γ-inducible protein 16 (IFI16) and cGMP-AMP synthase (cGAS) have both been proposed to detect herpesviral DNA directly in herpes simplex virus (HSV)-infected cells and initiate interferon regulatory factor-3 signaling, but it has been unclear how two DNA sensors could both be required for this response. We therefore investigated their relative roles in human foreskin fibroblasts (HFFs) infected with HSV or transfected with plasmid DNA. siRNA depletion studies showed that both are required for the production of IFN in infected HFFs. We found that cGAS shows low production of cGMP-AMP in infected cells, but instead cGAS is partially nuclear in normal human fibroblasts and keratinocytes, interacts with IFI16 in fibroblasts, and promotes the stability of IFI16. IFI16 is associated with viral DNA and targets to viral genome complexes, consistent with it interacting directly with viral DNA. Our results demonstrate that IFI16 and cGAS cooperate in a novel way to sense nuclear herpesviral DNA and initiate innate signaling.

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Kang, Won Sub, Su Kang Kim, and Hae Jeong Park. "Association of the Promoter Haplotype of IFN-γ-Inducible Protein 16 Gene with Schizophrenia in a Korean Population." Psychiatry Investigation 17, no. 2 (February 25, 2020): 140–46. http://dx.doi.org/10.30773/pi.2019.0175.

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Objective Viral infections play an important role in the development of schizophrenia, inducing the faulty immunological responses and aberrant inflammation. IFN-γ-inducible protein 16 (IFI16) is an immunological DNA sensor against viral infections, triggering the inflammatory responses. In this study, we investigated an association between putative promoter single nucleotide polymorphisms (SNPs) and haplotypes of IFI16 and schizophrenia.Methods A total of 280 schizophrenia patients and 427 control subjects were recruited in this study. We genotyped three promoter SNPs (rs1465175, rs3754464, rs1417806) using direct sequencing. Associations of SNPs and haplotypes of IFI16 with schizophrenia were analyzed. The promoter activities on the haplotypes of IFI16 were measured.Results The T allele of rs1465175 and the C allele of rs1417806 were protectively associated with schizophrenia (p=0.021 on rs1465175; p=0.016 on rs1417806), whereas the G allele of rs3754464 was associated with an increased risk of schizophrenia (p=0.019). In haplotype analysis, a significant association between the GGA haplotype and schizophrenia was shown (p=0.013). Moreover, we found that the GGA haplotype elevated the promoter activity compared to the GAA haplotype, whereas the TAC haplotype reduced that.Conclusion The promoter SNPs and haplotypes of IFI16 may contribute to the susceptibility of schizophrenia, affecting the promoter activity of IFI16.

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Marino, Sonia, Roberta Gualtierotti, Valeria Caneparo, Marco De Andrea, Marisa Gariglio, Pier Luigi Meroni, Eleonora Bossi, and Francesco Spadari. "IFI16 and Anti-IFI16 as Novel Biomarkers for Sjoegren’s Syndrome: Preliminary Data." Proceedings 35, no. 1 (December 11, 2019): 30. http://dx.doi.org/10.3390/proceedings2019035030.

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Justice, Joshua L., Michelle A. Kennedy, Josiah E. Hutton, Dawei Liu, Bokai Song, Brett Phelan, and Ileana M. Cristea. "Systematic profiling of protein complex dynamics reveals DNA-PK phosphorylation of IFI16 en route to herpesvirus immunity." Science Advances 7, no. 25 (June 2021): eabg6680. http://dx.doi.org/10.1126/sciadv.abg6680.

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Dynamically shifting protein-protein interactions (PPIs) regulate cellular responses to viruses and the resulting immune signaling. Here, we use thermal proximity coaggregation (TPCA) mass spectrometry to characterize the on-off behavior of PPIs during infection with herpes simplex virus 1 (HSV-1), a virus with an ancient history of coevolution with hosts. Advancing the TPCA analysis to infer associations de novo, we build a time-resolved portrait of thousands of host-host, virus-host, and virus-virus PPIs. We demonstrate that, early in infection, the DNA sensor IFI16 recruits the active DNA damage response kinase, DNA-dependent protein kinase (DNA-PK), to incoming viral DNA at the nuclear periphery. We establish IFI16 T149 as a substrate of DNA-PK upon viral infection or DNA damage. This phosphorylation promotes IFI16-driven cytokine responses. Together, we characterize the global dynamics of PPIs during HSV-1 infection, uncovering the co-regulation of IFI16 and DNA-PK functions as a missing link in immunity to herpesvirus infection.

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Helbi, Sobhan, Behnam Ravanbakhsh, Mohammad Karimi, Wesam Kooti, and Nahid Jivad. "Aligned Expression of IFI16 and STING Genes in RRMS Patients’ Blood." Endocrine, Metabolic & Immune Disorders - Drug Targets 20, no. 6 (July 17, 2020): 878–86. http://dx.doi.org/10.2174/1871530319666190729112246.

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Objective: Multiple sclerosis (MS) is a chronic neurodegenerative disease of the central nervous system. The most common disease phenotype is Relapsing-Remitting MS (RRMS). Beta interferons are the first line of RRMS patients’ treatment. Interferon-inducible protein 16 (IFI16) as a DNA sensing molecule and its downstream complex stimulator of interferon genes (STING) play a critical role in the activation of type I interferons. Hence we aimed to evaluate the expression rate of IFI16 and STING in RRMS patients’ blood under a different type of IFNβ treatment. Methods: In the present study, 99 individuals participated. The participants were divided into 4 groups: 28 control subjects, 25 new cases of RRMS patients, 25 RRMS patients treated with IFNβ-1a (B1a), 21 RRMS patients treated with IFNβ-1b (B1b). The EDTA-treated blood samples were taken and transferred at standard conditions to the Cellular and Molecular Research Center of Shahrekord University of Medical Sciences, RNA was extracted and converted into cDNA. To evaluate the expression of IFI16 and STING, the Real-Time PCR method using SYBR Green/ROX qPCR master mix was performed done. The level of genes expression was measured using 2–ΔΔCt method. The obtained data were analyzed using SPSS v22 software. Results: Comparison of the IFI and STING mRNA expression in blood samples in association with gender and age showed no significant differences (p>0.05). Also, the evaluation of IFI16 mRNA level revealed that the IFI16 genes’ expressions were remarkably higher in the new case group compared to the control group, however, STING expression did not show any significant difference. The mRNA levels of IFI16 and STING in IFNβ-treated groups were significantly lower than the new case group (p<0.001). Also, the genes’ expressions in both the IFNβ-treated groups were significantly lower compared to the control group (p<0.001). In the assessment of the correlation of IFI16 and STING expressions with age and sex in different research groups, no statistically significant differences were seen (p>0.05). Conclusion: Perhaps the IFNβ therapy decreases the IFI16 and STING expression in a STINGdependent pathway as a negative feedback mechanism for regulation of the immune system and suppression of pro-inflammatory cytokines production. The important role of DNA sensing molecules and STING-dependent pathway in MS gives a new insight into future treatment based on STING-direct therapies.

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Piccaluga, Pier Paolo, Claudio Agostinelli, Fabio Fuligni, Simona Righi, Claudio Tripodo, Maria Carla Re, Alberto Clò, et al. "IFI16Expression Is Related to Selected Transcription Factors during B-Cell Differentiation." Journal of Immunology Research 2015 (2015): 1–20. http://dx.doi.org/10.1155/2015/747645.

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The interferon-inducible DNA sensor IFI16 is involved in the modulation of cellular survival, proliferation, and differentiation. In the hematopoietic system, IFI16 is consistently expressed in the CD34+ stem cells and in peripheral blood lymphocytes; however, little is known regarding its regulation during maturation of B- and T-cells. We explored the role of IFI16 in normal B-cell subsets by analysing its expression and relationship with the major transcription factors involved in germinal center (GC) development and plasma-cell (PC) maturation.IFI16mRNA was differentially expressed in B-cell subsets with significant decrease inIFI16mRNA in GC and PCs with respect to naïve and memory subsets.IFI16mRNA expression is inversely correlated with a few master regulators of B-cell differentiation such asBCL6, XBP1, POU2AF1, andBLIMP1. In contrast,IFI16expression positively correlated withSTAT3, REL, SPIB, RELA, RELB, IRF4, STAT5B, andSTAT5A. ARACNE algorithm indicated a direct regulation ofIFI16byBCL6,STAT5B, andRELB, whereas the relationship betweenIFI16and the other factors is modulated by intermediate factors. In addition, analysis of the CD40 signaling pathway showed thatIFI16gene expression directly correlated with NF-κB activation, indicating that IFI16 could be considered an upstream modulator of NF-κB in human B-cells.

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Ortiz-Fernández, Lourdes, José-Raúl García-Lozano, Marco-Antonio Montes-Cano, Marta Conde-Jaldón, Norberto Ortego-Centeno, Francisco-José García-Hernández, Gerard Espinosa, et al. "Variants of the IFI16 Gene Affecting the Levels of Expression of mRNA Are Associated with Susceptibility to Behçet Disease." Journal of Rheumatology 42, no. 4 (February 1, 2015): 695–701. http://dx.doi.org/10.3899/jrheum.140949.

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Objective.Behçet disease (BD) is a multifactorial disease in which infectious agents have been proposed as triggers in genetically predisposed individuals. The aim of our study was to investigate the role of innate immunity receptors, specifically the nucleic acid sensors, in susceptibility to BD.Methods.Seventy-four tag single nucleotide polymorphisms (tSNP) selected in 9 candidate genes (DDX58, IFIH1, TLR3, TLR7, TLR8, AIM2, IFI16, ZBP1, and TLR9) were genotyped in 371 patients and 854 controls. Assays of mRNA expression and allele-specific transcript quantification (ASTQ) were performed in 110 and 50 controls, respectively.Results.Patients and controls were genotyped and 2 tSNP (rs6940 in IFI16 and rs855873 in AIM2) were associated with BD. To confirm this association, these tSNP were genotyped in 850 additional controls, and the total cohort was randomly divided into 2 cohorts. The association of these 2 tSNP with the disease remained in both cohorts. One haplotype (rs6940T-rs855873G) was identified as a risk factor (OR 1.41, 95% CI 1.06–1.86, p = 0.015), and another (rs6940A-rs855873A) as a protective factor (OR 0.65, 95% CI 0.47–0.90, p = 0.009). Samples with the risk haplotype had lower IFI16 expression levels than samples with the protective (0.99 ± 0.29 vs 1.23 ± 0.50, p = 0.022). Consistently, in the ASTQ assays performed with the nonsynonymous rs6940 SNP, the risk allele had lower IFI16 expression levels than the protective (p = 0.027).Conclusion.Our findings suggest association of IFI16, a cytosolic sensor of dsDNA and mediator of the AIM2 inflammasome-dependent pathway, in susceptibility to BD. Differences genetically determined in the levels of this molecule could be the cause of this association.

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Alimirah, Fatouma, Jianming Chen, Francesca J. Davis, and Divaker Choubey. "IFI16 in Human Prostate Cancer." Molecular Cancer Research 5, no. 3 (March 2007): 251–59. http://dx.doi.org/10.1158/1541-7786.mcr-06-0269.

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Cristea, Ileana M., Nathaniel J. Moorman, Scott S. Terhune, Christian D. Cuevas, Erin S. O'Keefe, Michael P. Rout, Brian T. Chait, and Thomas Shenk. "Human Cytomegalovirus pUL83 Stimulates Activity of the Viral Immediate-Early Promoter through Its Interaction with the Cellular IFI16 Protein." Journal of Virology 84, no. 15 (May 26, 2010): 7803–14. http://dx.doi.org/10.1128/jvi.00139-10.

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ABSTRACT The human cytomegalovirus (HCMV) virion protein pUL83 (also termed pp65) inhibits the expression of interferon-inducible cellular genes. In this work we demonstrate that pUL83 is also important for efficient induction of transcription from the viral major immediate-early promoter. Infection with a mutant virus containing a premature translation termination codon in the UL83 open reading frame (ORF) (UL83Stop) resulted in decreased transcription from the major immediate-early promoter in a time- and multiplicity-dependent manner. Expression of pUL83 alone is capable of transactivating the promoter in a reporter assay, and pUL83 associates with the promoter in infected cells. To investigate the mechanism by which the protein regulates the major immediate-early promoter, we utilized a mutant virus expressing an epitope-tagged pUL83 from its own promoter to identify protein binding partners for pUL83 during infection. We identified and confirmed the interaction of pUL83 with cellular IFI16 family members throughout the course of HCMV infection. pUL83 recruits IFI16 to the major immediate-early promoter, and IFI16 binding at the promoter is dependent upon the presence of pUL83. Consistent with the results obtained with the UL83Stop virus, infection of IFI16 knockdown cells with wild-type virus resulted in decreased levels of immediate-early transcripts compared to those of control cells. These data identify a previously unknown role for pUL83 in the initiation of the human cytomegalovirus gene expression cascade.

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Kerur, Nagaraj, Mohanan Veettil, Neelam Sharma-Walia, Virginie Bottero, Sathish Sadagopan, Pushpalatha Otageri, and Bala Chandran. "IFI16 acts as a nuclear danger sensor and induces the inflammasome in response to Kaposi’s sarcoma associated herpesvirus (KSHV) infection (157.8)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 157.8. http://dx.doi.org/10.4049/jimmunol.186.supp.157.8.

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Abstract Inflammasomes sense diverse classes of foreign molecules in the cytoplasm and induce caspase-1 activation and IL-1β maturation. Whether such a sensing mechanism exists in the nucleus is not known. Nuclear replicating herpesvirus KSHV is associated with Kaposi Sarcoma (KS) that is characterized by a microenvironment of inflammatory cytokines including IL-1β. How the caspase-1 inflammasome, which is required for IL-1β maturation is induced during KSHV infection is not known. Here we demonstrate that during de novo KSHV infection of endothelial cells, interferon gamma-inducible protein 16 (IFI16) interacts with ASC and procaspase-1 to form a functional inflammasome. This complex was initially detected in the nucleus and subsequently in the peri-nuclear area. Caspase-1 activation by KSHV was reduced by IFI16 and ASC silencing but not by AIM2 knockdown. Our studies reveal a new function of IFI16 as a nuclear danger sensor and demonstrate that the inflammasome’s danger sensing functions extend into the nucleus.

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Jin, Tengchuan, Andrew Perry, Jiansheng Jiang, Patrick Smith, James Curry, Leonie Unterholzner, Zhaozhao Jiang, et al. "Molecular mechanisms of Innate DNA recognition by the AIM2 and IFI16 inflammasomes (68.4)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 68.4. http://dx.doi.org/10.4049/jimmunol.188.supp.68.4.

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Søby, Stine, Rune R. Laursen, Lars Østergaard, and Jesper Melchjorsen. "HSV-1-induced chemokine expression via IFI16-dependent and IFI16-independent pathways in human monocyte-derived macrophages." Herpesviridae 3, no. 1 (2012): 6. http://dx.doi.org/10.1186/2042-4280-3-6.

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Ekabe, Cyril Jabea, Njinju Asaba Clinton, Jules Kehbila, and Ngangom Chouamo Franck. "The Role of Inflammasome Activation in Early HIV Infection." Journal of Immunology Research 2021 (September 20, 2021): 1–7. http://dx.doi.org/10.1155/2021/1487287.

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The inflammasome pathway is an important arm of the innate immune system that provides antiviral immunity against many viruses. The main pathways involved in virus infections include the NLRP3, IFI16, and AIM2 pathways. However, a succinct understanding of its role in HIV is not yet well elucidated. In this review, we showed that NLRP3 inflammasome activation plays a vital role in inhibiting HIV entry into target cells via the purinergic pathway; IFI16 detects intracellular HIV ssDNA, triggers interferon I and III production, and inhibits HIV transcription; and AIM2 binds to HIV dsDNA and triggers acute inflammation and pyroptosis. Remarkably, by understanding these mechanisms, new therapeutic strategies can be developed against the disease.

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Riva, Giuseppe, Matteo Biolatti, Giancarlo Pecorari, Valentina Dell’Oste, and Santo Landolfo. "PYHIN Proteins and HPV: Role in the Pathogenesis of Head and Neck Squamous Cell Carcinoma." Microorganisms 8, no. 1 (December 20, 2019): 14. http://dx.doi.org/10.3390/microorganisms8010014.

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In the last decades, the human papillomavirus (HPV) emerged as an etiological cause of head and neck squamous cell carcinoma (HNSCC), especially in the oropharynx. The role of two intracellular DNA sensors, which belong to the PYHIN family (interferon-inducible protein 16 (IFI16) and absent in melanoma 2 protein (AIM2)), has been analyzed in relation to HPV infection and head and neck carcinogenesis. In particular, IFI16 and AIM2 expression depends on HPV infection in HNSCC. They represent viral restriction factors and are key components of the intrinsic immunity activated against different viruses, including HPV. This review analyzed and summarized the recent findings about the role of PYHIN proteins in HPV+ and HPV− HNSCC.

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Fan, Xiaojiao, Jiansheng Jiang, Dan Zhao, Feng Chen, Huan Ma, Patrick Smith, Leonie Unterholzner, Tsan Sam Xiao, and Tengchuan Jin. "Structural mechanism of DNA recognition by the p204 HIN domain." Nucleic Acids Research 49, no. 5 (February 22, 2021): 2959–72. http://dx.doi.org/10.1093/nar/gkab076.

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Abstract The interferon gamma-inducible protein 16 (IFI16) and its murine homologous protein p204 function in non-sequence specific dsDNA sensing; however, the exact dsDNA recognition mechanisms of IFI16/p204, which harbour two HIN domains, remain unclear. In the present study, we determined crystal structures of p204 HINa and HINb domains, which are highly similar to those of other PYHIN family proteins. Moreover, we obtained the crystal structure of p204 HINab domain in complex with dsDNA and provided insights into the dsDNA binding mode. p204 HINab binds dsDNA mainly through α2 helix of HINa and HINb, and the linker between them, revealing a similar HIN:DNA binding mode. Both HINa and HINb are vital for HINab recognition of dsDNA, as confirmed by fluorescence polarization assays. Furthermore, a HINa dimerization interface was observed in structures of p204 HINa and HINab:dsDNA complex, which is involved in binding dsDNA. The linker between HINa and HINb reveals dynamic flexibility in solution and changes its direction at ∼90° angle in comparison with crystal structure of HINab:dsDNA complex. These structural information provide insights into the mechanism of DNA recognition by different HIN domains, and shed light on the unique roles of two HIN domains in activating the IFI16/p204 signaling pathway.

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Yu, Lili, Yongtao Xu, Fangchao Wang, Can Yang, Guoyan Liu, and Xiangfeng Song. "Functional Roles of Pattern Recognition Receptors That Recognize Virus Nucleic Acids in Human Adipose-Derived Mesenchymal Stem Cells." BioMed Research International 2016 (2016): 1–13. http://dx.doi.org/10.1155/2016/9872138.

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Human adipose-derived mesenchymal stem cells (hAD-MSCs) are mesenchymal stem cells with the capability to modulate immune responses. Evidence showing that hAD-MSCs could mediate innate immune responses through pattern recognition receptors (PRRs) is increasing. However, the roles of PRRs in regulating the innate sensing of virus nucleic acids (RNA and DNA) in hAD-MSCs have not yet been investigated. This study focused on the abundant expression of PRRs, including Toll-like receptor 3 (TLR3) and retinoic acid-inducible gene I (RIG-I), which recognize viral RNA, and gamma-interferon inducible protein 16 (IFI16), which recognizes viral DNA in hAD-MSCs. Poly(I:C), a synthetic dsRNA analogy, activated TLR3 and RIG-I and induced the expression of type I interferons (IFN-α/β) and antivirus proteins, including IFN-stimulating gene 15, 2′5′-oligoadenylate synthetase, and Mx GTPase 1 in hAD-MSCs, which were attenuated by the knockdown of each TLR3 or RIG-I. Synthetic herpes simplex viral DNA (HSV60) activated IFI16 and induced the expression of IFN-α/β and antivirus proteins in hAD-MSCs, which were inhibited by the knockdown of IFI16. Both poly(I:C) and HSV60 induced the expression of IFN-α/β through the phosphorylation of IFN-regulatory factor 3. All these results indicated that PRRs recognizing virus nucleic acids were expressed and can mediate antivirus responses in hAD-MSCs.

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Orzalli, M. H., N. A. DeLuca, and D. M. Knipe. "Nuclear IFI16 induction of IRF-3 signaling during herpesviral infection and degradation of IFI16 by the viral ICP0 protein." Proceedings of the National Academy of Sciences 109, no. 44 (October 1, 2012): E3008—E3017. http://dx.doi.org/10.1073/pnas.1211302109.

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Ouchi, Mutsuko. "Role of IFI16 in DNA damage and checkpoint." Frontiers in Bioscience 13, no. 13 (2008): 236. http://dx.doi.org/10.2741/2673.

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Bosso, Matteo, Caterina Prelli Bozzo, Meta Volcic, and Frank Kirchhoff. "IFI16 knockdown in primary HIV-1 target cells." STAR Protocols 2, no. 1 (March 2021): 100236. http://dx.doi.org/10.1016/j.xpro.2020.100236.

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Yan, Hongyue, Kush Dalal, Benjamin K. Hon, Philippe Youkharibache, Desmond Lau, and Frederic Pio. "RPA nucleic acid-binding properties of IFI16-HIN200." Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 1784, no. 7-8 (July 2008): 1087–97. http://dx.doi.org/10.1016/j.bbapap.2008.04.004.

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Unterholzner, Leonie, Sinead E. Keating, Marcin Baran, Kristy A. Horan, Søren B. Jensen, Shruti Sharma, Cherilyn M. Sirois, et al. "IFI16 is an innate immune sensor for intracellular DNA." Nature Immunology 11, no. 11 (October 3, 2010): 997–1004. http://dx.doi.org/10.1038/ni.1932.

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Packard, Thomas Alexander, Eytan Herzig, Xiaoyu Luo, Johanne H. Egedal, Zachary W. Grimmett, Kim J. Hasenkrug, Nadia Roan, and Warner C. Greene. "HIV-induced production of CCL2 may promote rapid seeding of the latent HIV reservoir." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 197.2. http://dx.doi.org/10.4049/jimmunol.202.supp.197.2.

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Abstract Seeding of the latent HIV reservoir occurs quickly within hours to a few days after initial viral infection. It is the persistence of virus within this reservoir that thwarts an HIV cure and necessitates life-long antiretroviral therapy (ART). Central memory CD4 T cells harboring latent HIV proviruses form a major part of this reservoir. How the virus establishes latency so rapidly within this subset of CD4 T cells remains unknown. We find that HIV infection leads to rapid production of the CCL2 chemokine in human lymphoid CD4 T cells. Cas9RNP-mediated depletion of IFI16 and STING genes significantly reduces production of CCL2 occurring in response to HIV. IFI16 was previously implicated as the key sensor triggering CD4 T cell pyroptosis. Thus, infection may also stimulate a second pathway of IFI16-mediated signaling involving STING culminating in CCL2 production. CCL2 functions a potent chemoattractant for cells expressing CCR2. Lymphoid CCR2+ CD4 T cells express the CCR5 co-receptor for HIV and markers of central memory. Additionally, these cells express many markers previously associated with the latent HIV reservoir. CCR2+ CD4 T cells are highly permissive to latent and productive infection by both R5 and X4-tropic viruses. When CCR2+ CD4 T cells are purified from HIV-infected individuals on suppressive ART, these cells are enriched up to 75-fold for HIV proviral DNA compared to naïve cells (n=10, p=0.0078). Together, our findings support a model where HIV infection triggers the production of CCL2, leading to directed recruitment and infection of CCR2+ CD4 central memory T cells. Thus, HIV hijacks a component of the innate immune response to rapidly recruit precisely those target cells that ensure its long term persistence.

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Everett, Roger D. "Dynamic Response of IFI16 and Promyelocytic Leukemia Nuclear Body Components to Herpes Simplex Virus 1 Infection." Journal of Virology 90, no. 1 (October 14, 2015): 167–79. http://dx.doi.org/10.1128/jvi.02249-15.

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ABSTRACTIntrinsic immunity is an aspect of antiviral defense that operates through diverse mechanisms at the intracellular level through a wide range of constitutively expressed cellular proteins. In the case of herpesviruses, intrinsic resistance involves the repression of viral gene expression during the very early stages of infection, a process that is normally overcome by viral tegument and/or immediate-early proteins. Thus, the balance between cellular repressors and virus-counteracting proteins determines whether or not a cell becomes productively infected. One aspect of intrinsic resistance to herpes simplex virus 1 (HSV-1) is conferred by components of promyelocytic leukemia nuclear bodies (PML NBs), which respond to infection by accumulating at sites that are closely associated with the incoming parental HSV-1 genomes. Other cellular proteins, including IFI16, which has been implicated in sensing pathogen DNA and initiating signaling pathways that lead to an interferon response, also respond to viral genomes in this manner. Here, studies of the dynamics of the response of PML NB components and IFI16 to invading HSV-1 genomes demonstrated that this response is extremely rapid, occurring within the first hour after addition of the virus, and that human Daxx (hDaxx) and IFI16 respond more rapidly than PML. In the absence of HSV-1 regulatory protein ICP0, which counteracts the recruitment process, the newly formed, viral-genome-induced PML NB-like foci can fuse with existing PML NBs. These data are consistent with a model involving viral genome sequestration into such structures, thereby contributing to the low probability of initiation of lytic infection in the absence of ICP0.IMPORTANCEHerpesviruses have intimate interactions with their hosts, with infection leading either to the productive lytic cycle or to a quiescent infection in which viral gene expression is suppressed while the viral genome is maintained in the host cell nucleus. Whether a cell becomes lytically or quiescently infected can be determined through the competing activities of cellular repressors and viral activators, some of which counteract cell-mediated repression. Therefore, the events that occur within the earliest stages of infection can be of crucial importance. This paper describes the extremely rapid response to herpes simplex virus 1 infection of cellular protein IFI16, a sensor of pathogen DNA, and also of the PML nuclear body proteins PML and hDaxx, as revealed by live-cell microscopy. The data imply that these proteins can accumulate on or close to the viral genomes in a sequential manner which may lead to their sequestration and repression.

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Qing, Jianbo, Wenzhu Song, Lingling Tian, Sonia Biju Samuel, and Yafeng Li. "Potential Small Molecules for Therapy of Lupus Nephritis Based on Genetic Effect and Immune Infiltration." BioMed Research International 2022 (April 23, 2022): 1–16. http://dx.doi.org/10.1155/2022/2259164.

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Lupus nephritis (LN) is the most common and significant complication of systemic lupus erythematosus (SLE) due to its poor prognosis and mortality rates in SLE patients. There is a critical need for new drugs as the pathogenesis of LN remains to be elucidated and immunosuppressive therapy comes with many deficiencies. In this study, 23 hub genes (IFI6, PLSCR1, XAF1, IFI16, IFI44, MX1, IFI44L, IFIT3, IFIT2, IFI27, DDX58, EIF2AK2, IFITM1, RTP4, IFITM3, TRIM22, PARP12, IFIH1, OAS1, HERC6, RSAD2, DDX60, and MX2) were identified through bioinformatics and network analysis and are closely related to interferon production and function. Interestingly, immune cell infiltration analysis and correlation analysis demonstrate a positive correlation between the expression of 23 hub genes and monocyte infiltration in glomeruli and M2 macrophage infiltration in the tubulointerstitium of LN patients. Additionally, the CTD database, DsigDB database, and DREIMT database were used to explore the bridging role of genes in chemicals and LN as well as the potential influence of these chemicals on immune cells. After comparison and discussion, six small molecules (Acetohexamide, Suloctidil, Terfenadine, Prochlorperazine, Mefloquine, and Triprolidine) were selected for their potential ability in treating lupus nephritis.

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Huang, Wenhui, Tingting Qian, Zeyong Huang, Yan Liu, Longzhen Cui, Pei Zhu, Qingfu Zhong, et al. "Increased expression of IFI16 predicts adverse prognosis in multiple myeloma." Pharmacogenomics Journal 21, no. 4 (March 12, 2021): 520–32. http://dx.doi.org/10.1038/s41397-021-00230-y.

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Choubey, Divaker. "Interferon-inducible IFI16 protein in human cancers and autoimmune diseases." Frontiers in Bioscience 13, no. 13 (2008): 598. http://dx.doi.org/10.2741/2705.

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Li, Dapei, Rongsheng Wu, Wen Guo, Lifen Xie, Zigang Qiao, Shengchuan Chen, Jingfei Zhu, et al. "STING-Mediated IFI16 Degradation Negatively Controls Type I Interferon Production." Cell Reports 29, no. 5 (October 2019): 1249–60. http://dx.doi.org/10.1016/j.celrep.2019.09.069.

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Stadion, Mandy, Kristin Schwerbel, Antonia Graja, Christian Baumeier, Maria Rödiger, Wenke Jonas, Christian Wolfrum, et al. "Increased Ifi202b/IFI16 expression stimulates adipogenesis in mice and humans." Diabetologia 61, no. 5 (February 24, 2018): 1167–79. http://dx.doi.org/10.1007/s00125-018-4571-9.

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Huérfano, Sandra, Vojtech Šroller, Kateřina Bruštíková, Lenka Horníková, and Jitka Forstová. "The Interplay between Viruses and Host DNA Sensors." Viruses 14, no. 4 (March 23, 2022): 666. http://dx.doi.org/10.3390/v14040666.

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DNA virus infections are often lifelong and can cause serious diseases in their hosts. Their recognition by the sensors of the innate immune system represents the front line of host defence. Understanding the molecular mechanisms of innate immunity responses is an important prerequisite for the design of effective antivirotics. This review focuses on the present state of knowledge surrounding the mechanisms of viral DNA genome sensing and the main induced pathways of innate immunity responses. The studies that have been performed to date indicate that herpesviruses, adenoviruses, and polyomaviruses are sensed by various DNA sensors. In non-immune cells, STING pathways have been shown to be activated by cGAS, IFI16, DDX41, or DNA-PK. The activation of TLR9 has mainly been described in pDCs and in other immune cells. Importantly, studies on herpesviruses have unveiled novel participants (BRCA1, H2B, or DNA-PK) in the IFI16 sensing pathway. Polyomavirus studies have revealed that, in addition to viral DNA, micronuclei are released into the cytosol due to genotoxic stress. Papillomaviruses, HBV, and HIV have been shown to evade DNA sensing by sophisticated intracellular trafficking, unique cell tropism, and viral or cellular protein actions that prevent or block DNA sensing. Further research is required to fully understand the interplay between viruses and DNA sensors.

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Kim, Marianne K.-H., Jacqueline M. Mason, Chi-Ming Li, Windy Berkofsky-Fessler, Le Jiang, Divaker Choubey, Paul E. Grundy, Benjamin Tycko, and Jonathan D. Licht. "A Pathologic Link between Wilms Tumor Suppressor Gene, WT1, and IFI16." Neoplasia 10, no. 1 (January 2008): 69—IN29. http://dx.doi.org/10.1593/neo.07869.

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Liu, Congcong, Ling Li, Gang Hou, Ying Lu, Meng Gao, and Lianwen Zhang. "HERC5/IFI16/p53 signaling mediates breast cancer cell proliferation and migration." Life Sciences 303 (August 2022): 120692. http://dx.doi.org/10.1016/j.lfs.2022.120692.

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Li, Ning, Yan Fu, Wei Chen, Gui-Qiu Hu, Min Zhou, Shui-Xing Yu, Xiao-Jing Zhang, Chong-Tao Du, and Yong-Jun Yang. "IFI16 mediates soluble Flt-1 and endoglin production by trophoblast cells." Journal of Hypertension 33, no. 8 (August 2015): 1658–65. http://dx.doi.org/10.1097/hjh.0000000000000605.

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Pollo, B., J. Mazibrada, C. Calatozzolo, F. Cacciatore, S. Spinello, V. Girgenti, F. Sciacca, G. Finocchiaro, S. Landolfo, and M. Patanè. "P06.15 IFI16 expression in gliomas and its potential role in immunosurveillance." Neuro-Oncology 18, suppl_4 (September 21, 2016): iv31. http://dx.doi.org/10.1093/neuonc/now188.106.

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Brázda, Václav, Jan Coufal, Jack C. C. Liao, and Cheryl H. Arrowsmith. "Preferential binding of IFI16 protein to cruciform structure and superhelical DNA." Biochemical and Biophysical Research Communications 422, no. 4 (June 2012): 716–20. http://dx.doi.org/10.1016/j.bbrc.2012.05.065.

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Jakobsen, Martin R., and Søren R. Paludan. "IFI16: At the interphase between innate DNA sensing and genome regulation." Cytokine & Growth Factor Reviews 25, no. 6 (December 2014): 649–55. http://dx.doi.org/10.1016/j.cytogfr.2014.06.004.

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Eriksson, Kristina, Alexandra Svensson, Alon S. Hait, Kerstin Schlüter, Petra Tunbäck, Inger Nordström, Leonid Padyukov, Jan-Åke Liljeqvist, Trine H. Mogensen, and Søren R. Paludan. "Cutting Edge: Genetic Association between IFI16 Single Nucleotide Polymorphisms and Resistance to Genital Herpes Correlates with IFI16 Expression Levels and HSV-2–Induced IFN-β Expression." Journal of Immunology 199, no. 8 (September 11, 2017): 2613–17. http://dx.doi.org/10.4049/jimmunol.1700385.

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Kim, Hyungsoo, Heejung Kim, Yongmei Feng, Yan Li, Hironari Tamiya, Stefania Tocci, and Ze’ev A. Ronai. "PRMT5 control of cGAS/STING and NLRC5 pathways defines melanoma response to antitumor immunity." Science Translational Medicine 12, no. 551 (July 8, 2020): eaaz5683. http://dx.doi.org/10.1126/scitranslmed.aaz5683.

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Protein arginine methyltransferase 5 (PRMT5) controls diverse cellular processes and is implicated in cancer development and progression. Here, we report an inverse correlation between PRMT5 function and antitumor immunity. PRMT5 expression was associated with an antitumor immune gene signature in human melanoma tissue. Reducing PRMT5 activity antagonized melanoma growth in immunocompetent but not immunocompromised mice. PRMT5 methylation of IFI16 [interferon-γ (IFN-γ)–inducible protein 16] or its murine homolog IFI204, which are components of the cGAS/STING (stimulator of IFN genes) pathway, attenuated cytosolic DNA–induced IFN and chemokine expression in melanoma cells. PRMT5 also inhibited transcription of the gene encoding NLRC5 (nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 5), a protein that promotes the expression of genes implicated in major histocompatibility complex class I (MHCI) antigen presentation. PRMT5 knockdown augmented IFN and chemokine production and increased MHCI abundance in melanoma. Increased expression of IFI204 and NLRC5 was associated with decreased melanoma growth in murine models, and increased expression of IFI16 and NLRC5 correlated with prolonged survival of patients with melanoma. Combination of pharmacological (GSK3326595) or genetic (shRNA) inhibition of PRMT5 with immune checkpoint therapy limited growth of murine melanoma tumors (B16F10 and YUMM1.7) and enhanced therapeutic efficacy, compared with the effect of either treatment alone. Overall, our findings provide a rationale to test PRMT5 inhibitors in immunotherapy-based clinical trials as a means to enhance an antitumor immune response.

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Gray, Elizabeth, and Daniel B. Stetson. "The AIM2-like receptors are dispensable for activation of the interferon stimulatory DNA (ISD) pathway." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 203.10. http://dx.doi.org/10.4049/jimmunol.196.supp.203.10.

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Abstract:

Abstract Detection of intracellular DNA triggers activation of the STING-dependent interferon-stimulatory DNA (ISD) pathway, which is essential for antiviral immune responses; on the other hand, inappropriate immune responses to self DNA result in autoimmunity. Multiple DNA sensors have been proposed to activate the ISD pathway, including cyclic GMP-AMP synthase (cGAS) and a family of DNA binding receptors called the AIM2-like receptors (ALRs). Analysis of cGAS-deficient mice has revealed that cGAS is a key DNA sensor that is required for activation of the ISD pathway; however, whether the ALRs contribute to this pathway remains unclear. Here, we generated mice lacking all 13 mouse ALR genes as a novel tool to explore the function of the ALRs. We show that all ALRs are dispensable for the type I interferon (IFN) response to transfected DNA ligands, DNA virus infection, and lentivirus infection. We also show that the DNA sensor cGAS, but not the ALRs, is required to drive autoimmune disease in the Trex1-deficient mouse model of Aicardi-Goutieres Syndrome. Finally, we used CRISPR to disrupt the human AIM2-like receptor IFI16 in primary human fibroblasts and show that IFI16 is dispensable for the IFN response to transfected DNA ligands as well as human cytomegalovirus (HCMV) infection. Thus, our data reveal that ALRs are dispensable for activation of the ISD pathway and demonstrate that cGAS is the primary DNA sensor that drives the IFN response to DNA.

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Journal articles on the topic 'IFI16'

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