The Experts below are selected from a list of 40188 Experts worldwide ranked by ideXlab platform
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.
Michael S. Diamond - One of the best experts on this subject based on the ideXlab platform.
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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.
Daniel J Mathew - One of the best experts on this subject based on the ideXlab platform.
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conceptus induced interferon tau dependent gene expression in bovine endometrial epithelial and stromal cells
Biology of Reproduction, 2021Co-Authors: Heather L Chaney, Thomas E Spencer, P Lonergan, Gilles Charpigny, Susanta K Behura, Lindsay F Grose, Martin I Sheldon, James G Cronin, Daniel J MathewAbstract:Bovine endometrium consists of epithelial and stromal cells that respond to conceptus interferon tau (IFNT), the maternal recognition of pregnancy (MRP) signal, by increasing expression of IFN-stimulated genes (ISGs). Endometrial epithelial and stromal cell specific ISGs are largely unknown but hypothesized to have essential functions during pregnancy establishment. Bovine endometrial epithelial cells were cultured in inserts above stromal fibroblast (SF) cells for 6 h in medium alone or with IFNT. The epithelial and SF transcriptomic response was analyzed separately using RNA sequencing and compared to a list of 369 DEGs recently identified in intact bovine endometrium in response to elongating bovine conceptuses and IFNT. Bovine endometrial epithelial and SF shared 223 and 70 DEGs in common with the list of 369 endometrial DEGs. Well known ISGs identified in the epithelial and SF were ISG15, MX1, MX2, and OAS2. DEGs identified in the epithelial but not SF included a number of IRF molecules (IRF1, IRF2, IRF3 and IRF8), mitochondria SLC transporters (SLC25A19, SLC25A28 and SLC25A30), and a ghrelin receptor (GHSR). Expression of ZC3HAV1, an anti-retroviral gene, increased specifically within the SF. Gene ontology analysis identified the type I IFN signaling pathway and activation of nuclear factor kappa B transcription factors as biological processes associated with the epithelial cell DEGs. This study has identified biologically relevant IFNT stimulated genes within specific endometrial cell types. The findings provide critical information regarding the effects of conceptus IFNT on specific endometrial compartments during early developmental processes in cattle.
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.
