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Wuhan Xiao - One of the best experts on this subject based on the ideXlab platform.
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correction zebrafish f box protein fbxo3 negatively regulates antiviral response through promoting k27 linked polyubiquitination of the transcription factors irf3 and IRF7
Journal of Immunology, 2021Co-Authors: Sijia Fan, Xiaoyun Chen, Qian Liao, Xing Liu, Gang Ouyang, Hong Cao, Jing Wang, Wuhan XiaoAbstract:FBXO3, belongs to the F-box family of proteins, which has been reported to involve in host autoimmune and inflammatory responses by promoting its substrates for ubiquitylation. However, thus far, its physiological function in antiviral immunity remains elusive. In this study, we report that overexpression of zebrafish fbxo3 suppresses cellular antiviral responses. Moreover, disruption of fbxo3 in zebrafish increases the survival rate upon spring viremia of carp virus exposure. Further assays indicate that fbxo3 interacts with irf3/IRF7 and specifically catalyzes K27-linked ubiquitination of irf3 and IRF7, resulting in proteasomal degradation of irf3 and IRF7. However, the F-box domain of fbxo3 is not required for fbxo3 to interact with irf3/IRF7 and to inhibit transactivity of irf3 and IRF7. This study provides novel insights into fbxo3 function and the underlying mechanisms. In addition, it sheds new light on the regulation of IFN-I signaling by F-box proteins.
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zebrafish otud6b negatively regulates antiviral responses by suppressing k63 linked ubiquitination of irf3 and IRF7
Journal of Immunology, 2021Co-Authors: Ziwen Zhou, Xing Liu, Gang Ouyang, Xiaolian Cai, Junji Zhu, Wuhan XiaoAbstract:Ovarian tumor domain-containing 6B (OTUD6B) belongs to the OTU deubiquitylating enzyme family. In this study, we report that zebrafish otud6b is induced upon viral infection, and overexpression of otud6b suppresses cellular antiviral response. Disruption of otud6b in zebrafish increases the survival rate upon spring viremia of carp virus and grass carp reovirus exposure. Further assays indicate that otud6b interacts with irf3 and IRF7 and diminishes traf6-mediated K63-linked polyubiquitination of irf3 and IRF7. In addition, the OTU domain is required for otud6b to repress IFN-1 activation and K63-linked polyubiquitination of irf3 and IRF7. Moreover, otud6b also attenuates tbk1 to bind to irf3 and IRF7, resulting in the impairment of irf3 and IRF7 phosphorylation. This study provides, to our knowledge, novel insights into otud6b function and sheds new lights on the regulation of irf3 and IRF7 by deubiquitination in IFN-1 signaling.
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Zebrafish F-box Protein fbxo3 Negatively Regulates Antiviral Response through Promoting K27-Linked Polyubiquitination of the Transcription Factors irf3 and IRF7.
The Journal of Immunology, 2020Co-Authors: Sijia Fan, Jian Wang, Xiaoyun Chen, Qian Liao, Xing Liu, Gang Ouyang, Hong Cao, Wuhan XiaoAbstract:FBXO3, belongs to the F-box family of proteins, which has been reported to involve in host autoimmune and inflammatory responses by promoting its substrates for ubiquitylation. However, thus far, its physiological function in antiviral immunity remains elusive. In this study, we report that overexpression of zebrafish fbxo3 suppresses cellular antiviral responses. Moreover, disruption of fbxo3 in zebrafish increases the survival rate upon spring viremia of carp virus exposure. Further assays indicate that fbxo3 interacts with irf3/IRF7 and specifically catalyzes K27-linked ubiquitination of irf3 and IRF7, resulting in proteasomal degradation of irf3 and IRF7. However, the F-box domain of fbxo3 is not required for fbxo3 to interact with irf3/IRF7 and to inhibit transactivity of irf3 and IRF7. This study provides novel insights into fbxo3 function and the underlying mechanisms. In addition, it sheds new light on the regulation of IFN-I signaling by F-box proteins.
John T. Patton - One of the best experts on this subject based on the ideXlab platform.
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rotavirus nsp1 mediates degradation of interferon regulatory factors through targeting of the dimerization domain
Journal of Virology, 2013Co-Authors: Michelle M Arnold, Mario Barro, John T. PattonAbstract:Rotavirus nonstructural protein NSP1 can inhibit expression of interferon (IFN) and IFN-stimulated gene products by inducing proteasome-mediated degradation of IFN-regulatory factors (IRFs), including IRF3, IRF5, and IRF7. All IRF proteins share an N-terminal DNA-binding domain (DBD), and IRF3, IRF5, and IRF7 contain a similar C-proximal IRF association domain (IAD) that mediates IRF dimerization. An autoinhibitory domain (ID) at the extreme C terminus interacts with the IAD, burying residues necessary for IRF dimerization. Phosphorylation of serine/threonine residues in the ID induces charge repulsions that unmask the IAD, enabling IRF dimerization and subsequent nuclear translocation. To define the region of IRF proteins targeted for degradation by NSP1, we generated IRF3 and IRF7 truncation mutants and transiently expressed each with simian SA11-4F NSP1. These assays indicated that the IAD represented a necessary and sufficient target for degradation. Because NSP1 did not mediate degradation of truncated forms of the IAD, NSP1 likely requires a structurally intact IAD for recognition and targeting of IRF proteins. IRF9, which contains an IAD-like region that directs interactions with signal inducer and activator of transcription (STAT) proteins, was also targeted for degradation by NSP1, while IRF1, which lacks an IAD, was not. Analysis of mutant forms of IRF3 unable to undergo dimerization or that were constitutively dimeric showed that both were targeted for degradation by NSP1. These results indicate that SA11-4F NSP1 can induce degradation of inactive and activated forms of IAD-containing IRF proteins (IRF3 to IRF9), allowing a multipronged attack on IFN-based pathways that promote antiviral innate and adaptive immune responses.
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Rotavirus NSP1 Inhibits Expression of Type I Interferon by Antagonizing the Function of Interferon Regulatory Factors IRF3, IRF5, and IRF7
Journal of Virology, 2007Co-Authors: Mario Barro, John T. PattonAbstract:Secretion of interferon (IFN) by virus-infected cells is essential for activating autocrine and paracrine pathways that promote cellular transition to an antiviral state. In most mammalian cells, IFN production is initiated by the activation of constitutively expressed IFN regulatory factor 3, IRF3, which in turn leads to the induction of IRF7, the “master regulator” of IFN type I synthesis (alpha/beta IFN). Previous studies established that rotavirus NSP1 antagonizes IFN signaling by inducing IRF3 degradation. In the present study, we have determined that, in comparison to wild-type rotaviruses, rotaviruses encoding defective NSP1 grow to lower titers in some cell lines and that this poor growth phenotype is due to their failure to suppress IFN expression. Furthermore, we provide evidence that rotaviruses encoding wild-type NSP1 subvert IFN signaling by inducing the degradation of not only IRF3, but also IRF7, with both events occurring through proteasome-dependent processes that proceed with similar efficiencies. The capacity of NSP1 to induce IRF7 degradation may allow rotavirus to move across the gut barrier by enabling the virus to replicate in specialized trafficking cells (dendritic cells and macrophages) that constitutively express IRF7. Along with IRF3 and IRF7, NSP1 was found to induce the degradation of IRF5, a factor that upregulates IFN expression and that is involved in triggering apoptosis during viral infection. Our analysis suggests that NSP1 mediates the degradation of IRF3, IRF5, and IRF7 by recognizing a common element of IRF proteins, thereby allowing NSP1 to act as a broad-spectrum antagonist of IRF function.
You Zhou - One of the best experts on this subject based on the ideXlab platform.
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the infected cell protein 0 encoded by bovine herpesvirus 1 bicp0 associates with interferon regulatory factor 7 and consequently inhibits beta interferon promoter activity
Journal of Virology, 2009Co-Authors: Kazima Saira, You Zhou, Clinton JonesAbstract:The bICP0 protein encoded by bovine herpesvirus 1 stimulates productive infection and viral gene expression but inhibits interferon (IFN)-dependent transcription. bICP0 inhibits beta IFN (IFN-β) promoter activity and induces degradation of IFN regulatory factor 3 (IRF3). Although bICP0 inhibits the trans-activation activity of IRF7, IRF7 protein levels are not reduced. In this study, we demonstrate that bICP0 is associated with IRF7. Furthermore, bICP0 inhibits the ability of IRF7 to trans-activate the IFN-β promoter in the absence of IRF3 expression. The interaction between bICP0 and IRF7 correlates with reduced trans-activation of the IFN-β promoter by IRF7.
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the infected cell protein 0 encoded by bovine herpesvirus 1 bicp0 induces degradation of interferon response factor 3 and consequently inhibits beta interferon promoter activity
Journal of Virology, 2007Co-Authors: Kazima Saira, You ZhouAbstract:The ICP0 protein (bICP0) encoded by bovine herpesvirus 1 is the major viral regulatory protein because it stimulates all viral promoters and, consequently, productive infection. Like other ICP0 analogues encoded by Alphaherpesvirinae subfamily members, bICP0 contains a zinc RING finger near its amino terminus that is necessary for activating transcription, regulating subcellular localization, and inhibiting interferon-dependent transcription. In this study, we discovered that sequences near the C terminus, and the zinc RING finger, are necessary for inhibiting the human beta interferon (IFN-β) promoter. In contrast to herpes simplex virus type 1-encoded ICP0, bICP0 reduces interferon response factor 3 (IRF3), but not IRF7, protein levels in transiently transfected cells. The zinc RING finger and sequences near the C terminus are necessary for bICP0-induced degradation of IRF3. A proteasome inhibitor, lactacystin, interfered with bICP0-induced degradation of IRF3, suggesting that bICP0, directly or indirectly, targets IRF3 for proteasome-dependent degradation. IRF3, but not IRF7, is not readily detectable in the nuclei of productively infected bovine cells during the late stages of infection. In the context of productive infection, IRF3 and IRF7 are detected in the nucleus at early times after infection. At late times after infection, IRF7, but not IRF3, is still detectable in the nuclei of infected cells. Collectively, these studies suggest that the ability of bICP0 to reduce IRF3 protein levels is important with respect to disarming the IFN response during productive infection.
Kazima Saira - One of the best experts on this subject based on the ideXlab platform.
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the infected cell protein 0 encoded by bovine herpesvirus 1 bicp0 associates with interferon regulatory factor 7 and consequently inhibits beta interferon promoter activity
Journal of Virology, 2009Co-Authors: Kazima Saira, You Zhou, Clinton JonesAbstract:The bICP0 protein encoded by bovine herpesvirus 1 stimulates productive infection and viral gene expression but inhibits interferon (IFN)-dependent transcription. bICP0 inhibits beta IFN (IFN-β) promoter activity and induces degradation of IFN regulatory factor 3 (IRF3). Although bICP0 inhibits the trans-activation activity of IRF7, IRF7 protein levels are not reduced. In this study, we demonstrate that bICP0 is associated with IRF7. Furthermore, bICP0 inhibits the ability of IRF7 to trans-activate the IFN-β promoter in the absence of IRF3 expression. The interaction between bICP0 and IRF7 correlates with reduced trans-activation of the IFN-β promoter by IRF7.
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the infected cell protein 0 encoded by bovine herpesvirus 1 bicp0 induces degradation of interferon response factor 3 and consequently inhibits beta interferon promoter activity
Journal of Virology, 2007Co-Authors: Kazima Saira, You ZhouAbstract:The ICP0 protein (bICP0) encoded by bovine herpesvirus 1 is the major viral regulatory protein because it stimulates all viral promoters and, consequently, productive infection. Like other ICP0 analogues encoded by Alphaherpesvirinae subfamily members, bICP0 contains a zinc RING finger near its amino terminus that is necessary for activating transcription, regulating subcellular localization, and inhibiting interferon-dependent transcription. In this study, we discovered that sequences near the C terminus, and the zinc RING finger, are necessary for inhibiting the human beta interferon (IFN-β) promoter. In contrast to herpes simplex virus type 1-encoded ICP0, bICP0 reduces interferon response factor 3 (IRF3), but not IRF7, protein levels in transiently transfected cells. The zinc RING finger and sequences near the C terminus are necessary for bICP0-induced degradation of IRF3. A proteasome inhibitor, lactacystin, interfered with bICP0-induced degradation of IRF3, suggesting that bICP0, directly or indirectly, targets IRF3 for proteasome-dependent degradation. IRF3, but not IRF7, is not readily detectable in the nuclei of productively infected bovine cells during the late stages of infection. In the context of productive infection, IRF3 and IRF7 are detected in the nucleus at early times after infection. At late times after infection, IRF7, but not IRF3, is still detectable in the nuclei of infected cells. Collectively, these studies suggest that the ability of bICP0 to reduce IRF3 protein levels is important with respect to disarming the IFN response during productive infection.
Michael S. Diamond - One of the best experts on this subject based on the ideXlab platform.
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an irf 3 irf 5 and irf 7 independent pathway of dengue viral resistance utilizes irf 1 to stimulate type i and ii interferon responses
Cell Reports, 2017Co-Authors: Aaron F Carlin, Emily M Plummer, Edward A Vizcarra, Nicholas Sheets, Yunichel Joo, William W Tang, Jeremy Day, J Greenbaum, Christopher K Glass, Michael S. DiamondAbstract:Interferon-regulatory factors (IRFs) are a family of transcription factors (TFs) that translate viral recognition into antiviral responses, including type I interferon (IFN) production. Dengue virus (DENV) and other clinically important flaviviruses are suppressed by type I IFN. While mice lacking the type I IFN receptor (Ifnar1-/-) succumb to DENV infection, we found that mice deficient in three transcription factors controlling type I IFN production (Irf3-/-Irf5-/-IRF7-/- triple knockout [TKO]) survive DENV challenge. DENV infection of TKO mice resulted in minimal type I IFN production but a robust type II IFN (IFN-γ) response. Using loss-of-function approaches for various molecules, we demonstrate that the IRF-3-, IRF-5-, IRF-7-independent pathway predominantly utilizes IFN-γ and, to a lesser degree, type I IFNs. This pathway signals via IRF-1 to stimulate interleukin-12 (IL-12) production and IFN-γ response. These results reveal a key antiviral role for IRF-1 by activating both type I and II IFN responses during DENV infection.
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a mouse model of zika virus pathogenesis
Cell Host & Microbe, 2016Co-Authors: Jennifer Govero, Jerome James Miner, Derek J Platt, Amber M Smith, Estefania Fernandez, Michael S. DiamondAbstract:Summary The ongoing Zika virus (ZIKV) epidemic and unexpected clinical outcomes, including Guillain-Barre syndrome and birth defects, has brought an urgent need for animal models. We evaluated infection and pathogenesis with contemporary and historical ZIKV strains in immunocompetent mice and mice lacking components of the antiviral response. Four- to six-week-old Irf3 −/− Irf5 −/− IRF7 −/− triple knockout mice, which produce little interferon α/β, and mice lacking the interferon receptor ( Ifnar1 −/− ) developed neurological disease and succumbed to ZIKV infection, whereas single Irf3 −/− , Irf5 −/− , and Mavs −/− knockout mice exhibited no overt illness. Ifnar1 −/− mice sustained high viral loads in the brain and spinal cord, consistent with evidence that ZIKV causes neurodevelopmental defects in human fetuses. The testes of Ifnar1 −/− mice had the highest viral loads, which is relevant to sexual transmission of ZIKV. This model of ZIKV pathogenesis will be valuable for evaluating vaccines and therapeutics as well as understanding disease pathogenesis.
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Interferon-Regulatory Factor 5-Dependent Signaling Restricts Orthobunyavirus Dissemination to the Central Nervous System
Journal of Virology, 2015Co-Authors: José Luiz Proença-módena, Amelia K Pinto, Justin M Richner, Tiffany M Lucas, Jennifer L Hyde, Renata Sesti-costa, Matthew J. Gorman, Michael S. DiamondAbstract:Interferon (IFN)-regulatory factor 5 (IRF-5) is a transcription factor that induces inflammatory responses after engagement and signaling by pattern recognition receptors. To define the role of IRF-5 during bunyavirus infection, we evaluated Oropouche virus (OROV) and La Crosse virus (LACV) pathogenesis and immune responses in primary cells and in mice with gene deletions in Irf3, Irf5, and IRF7 or in Irf5 alone. Deletion of Irf3, Irf5, and IRF7 together resulted in uncontrolled viral replication in the liver and spleen, hypercytokinemia, extensive liver injury, and an early-death phenotype. Remarkably, deletion of Irf5 alone resulted in meningoencephalitis and death on a more protracted timeline, 1 to 2 weeks after initial OROV or LACV infection. The clinical signs in OROV-infected Irf5−/− mice were associated with abundant viral antigen and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL)-positive cells in several regions of the brain. Circulating dendritic cell (DC) subsets in Irf5−/− mice had higher levels of OROV RNA in vivo yet produced lower levels of type I IFN than wild-type (WT) cells. This result was supported by data obtained in vitro, since a deficiency of IRF-5 resulted in enhanced OROV infection and diminished type I IFN production in bone marrow-derived DCs. Collectively, these results indicate a key role for IRF-5 in modulating the host antiviral response in peripheral organs that controls bunyavirus neuroinvasion in mice. IMPORTANCE Oropouche virus (OROV) and La Crosse virus (LACV) are orthobunyaviruses that are transmitted by insects and cause meningitis and encephalitis in subsets of individuals in the Americas. Recently, we demonstrated that components of the type I interferon (IFN) induction pathway, particularly the regulatory transcription factors IRF-3 and IRF-7, have key protective roles during OROV infection. However, the lethality in Irf3−/− IRF7−/− (DKO) mice infected with OROV was not as rapid or complete as observed in Ifnar−/− mice, indicating that other transcriptional factors associated with an IFN response contribute to antiviral immunity against OROV. Here, we evaluated bunyavirus replication, tissue tropism, and cytokine production in primary cells and mice lacking IRF-5. We demonstrate an important role for IRF-5 in preventing neuroinvasion and the ensuing encephalitis caused by OROV and LACV.
