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Curt M Horvath - One of the best experts on this subject based on the ideXlab platform.
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Transcriptional regulation by STAT1 and STAT2 in the interferon JAK-STAT pathway
JAK-STAT, 2013Co-Authors: Nancy Au-yeung, Roli Mandhana, Curt M HorvathAbstract:STAT1 and STAT2 proteins are key mediators of type I and type III interferon (IFN) signaling, and are essential components of the cellular antiviral response and adaptive immunity. They associate with IFN regulatory factor 9 (IRF9) to form a heterotrimeric transcription factor complex known as ISGF3. The regulation of IFN-stimulated gene (ISG) expression has served as a model of JAK-STAT signaling and mammalian transcriptional regulation, but to date has primarily been analyzed at the single gene level. While many aspects of ISGF3-mediated gene regulation are thought to be common features applicable to several ISGs, there are also many reports of distinct cases of non-canonical STAT1 or STAT2 signaling events and distinct patterns of co-regulators that contribute to gene-specific transcription. Recent genome-wide studies have begun to uncover a more complete profile of ISG regulation, moving toward a genome-wide understanding of general mechanisms that underlie gene-specific behaviors.
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A Point Mutation, E95D, in the Mumps Virus V Protein Disengages STAT3 Targeting from STAT1 Targeting
Journal of Virology, 2009Co-Authors: Mamta Puri, W. Paul Duprex, Bertus K. Rima, Ken Lemon, Curt M HorvathAbstract:Mumps virus, like other paramyxoviruses in the Rubulavirus genus, encodes a V protein that can assemble a ubiquitin ligase complex from cellular components, leading to the destruction of cellular signal transducer and activator of transcription (STAT) proteins. While many V proteins target the interferon-activated STAT1 or STAT2 protein, mumps virus V protein is unique in its ability to also target STAT3 for ubiquitin modification and proteasome-mediated degradation. Here we report that a single amino acid substitution in the mumps virus V protein, E95D, results in defective STAT3 targeting while maintaining the ability to target STAT1. Results indicate that the E95D mutation disrupts the ability of the V protein to associate with STAT3. A recombinant mumps virus carrying the E95D mutation in its P and V proteins replicates normally in cultured cells but fails to induce targeting of STAT3. Infection with the recombinant virus results in the differential regulation of a number of cellular genes compared to wild-type mumps virus and increases cell death in infected cells, producing a large-plaque phenotype.
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Composition and assembly of STAT-targeting ubiquitin ligase complexes: paramyxovirus V protein carboxyl terminus is an oligomerization domain.
Journal of Virology, 2005Co-Authors: Christina M. Ulane, Alex Kentsis, Cristian D. Cruz, Jean Patrick Parisien, Kristi L. Schneider, Curt M HorvathAbstract:Transcription regulators STAT1 and STAT2 are key components of the interferon signaling system leading to innate antiviral immunity. The related STAT3 protein is a regulator of interleukin-6-type cytokine signals and can contribute to both cell growth and death important for cancer gene regulation and tumor survival. These three STAT proteins are targeted for proteasome-mediated degradation by RNA viruses in the Rubulavirus genus of the Paramyxoviridae. A single viral protein, the V protein, assembles STAT-specific ubiquitin ligase complexes from cellular components. Simian virus 5 (SV5) targets STAT1, human parainfluenza virus 2 targets STAT2, and mumps virus targets both STAT1 and STAT3. Analysis of the V-dependent degradation complex (VDC) composition and assembly revealed several features contributing to targeting specificity. SV5 and mumps V proteins require STAT2 to recruit the STAT1 target, yet mumps V protein binds STAT3 independent of STAT1 and STAT2. All Rubulavirus V proteins tested require cellular DDB1 to target STATs for degradation but differ in the use of Roc1, which is essential for mumps V STAT3 targeting. Protein interaction analysis reveals that paramyxovirus V proteins can homo- and heterooligomerize and that the conserved cysteine-rich zinc-binding C-terminal domain is necessary and sufficient for oligomerization. Purified SV5 V protein spontaneously assembles into spherical macromolecular particles, and similar particles constitute SV5 and mumps VDC preparations.
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hendra virus v protein inhibits interferon signaling by preventing stat1 and STAT2 nuclear accumulation
Journal of Virology, 2003Co-Authors: Jason J. Rodriguez, Lin Fa Wang, Curt M HorvathAbstract:The V protein of the recently emerged paramyxovirus, Nipah virus, has been shown to inhibit interferon (IFN) signal transduction through cytoplasmic sequestration of cellular STAT1 and STAT2 in high-molecular-weight complexes. Here we demonstrate that the closely related Hendra virus V protein also inhibits cellular responses to IFN through binding and cytoplasmic sequestration of both STAT1 and STAT2, but not STAT3. These findings demonstrate a V protein-mediated IFN signal evasion mechanism that is a general property of the known Henipavirus species.
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STAT3 ubiquitylation and degradation by mumps virus suppress cytokine and oncogene signaling.
Journal of Virology, 2003Co-Authors: Christina M. Ulane, Jean Patrick Parisien, Jason J. Rodriguez, Curt M HorvathAbstract:Mumps virus is a common infectious agent of humans, causing parotitis, meningitis, encephalitis, and orchitis. Like other paramyxoviruses in the genus Rubulavirus, mumps virus catalyzes the proteasomal degradation of cellular STAT1 protein, a means for escaping antiviral responses initiated by alpha/beta and gamma interferons. We demonstrate that mumps virus also eliminates cellular STAT3, a protein that mediates transcriptional responses to cytokines, growth factors, nonreceptor tyrosine kinases, and a variety of oncogenic stimuli. STAT1 and STAT3 are independently targeted by a single mumps virus protein, called V, that assembles STAT-directed ubiquitylation complexes from cellular components, including STAT1, STAT2, STAT3, DDB1, and Cullin4A. Consequently, mumps virus V protein prevents responses to interleukin-6 and v-Src signals and can induce apoptosis in STAT3-dependent multiple myeloma cells and transformed murine fibroblasts. These findings demonstrate a unique cytokine and oncogene evasion property of mumps virus that provides a molecular basis for its observed oncolytic properties.
Eleanor N. Fish - One of the best experts on this subject based on the ideXlab platform.
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The interferon-inducible STAT2:Stat1 heterodimer preferentially binds in vitro to a consensus element found in the promoters of a subset of interferon-stimulated genes.
Journal of Interferon and Cytokine Research, 2001Co-Authors: Julien Ghislain, Melody Nguyen, Thomas Wong, Eleanor N. FishAbstract:Regulated expression of type I interferon (IFN)-stimulated genes (ISG) requires the binding of the signal transducer and activator of transcription (Stat) complexes to enhancer elements located in the ISG promoters. These enhancer elements include the IFN-stimulated response element (ISRE) and the palindromic IFN-γ activation site (GAS) element. Regulated expression of ISRE containing ISG depends on IFN-stimulated gene factor 3 (ISGF3), a heterodimer involving Stat1 and STAT2 in association with a DNA-binding adapter protein, p48/IFN regulatory factor-9 (IRF-9). Several GAS binding Stat complexes involving Stat1, Stat3, Stat4, and Stat5 have been described, but their contribution to GAS-dependent ISG expression remains to be established. We and others previously identified an IFN-α-inducible STAT2:1 heterodimer that exhibits binding to the GAS element of the IRF-1 gene. These previous studies raise the possibility that STAT2:1 may participate in the transcriptional activation of the subset of ISG containi...
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The interferon-inducible STAT2:Stat1 heterodimer preferentially binds in vitro to a consensus element found in the promoters of a subset of interferon-stimulated genes.
Journal of Interferon and Cytokine Research, 2001Co-Authors: Julien Ghislain, Melody Nguyen, Thomas Wong, Eleanor N. FishAbstract:Regulated expression of type I interferon (IFN)-stimulated genes (ISG) requires the binding of the signal transducer and activator of transcription (Stat) complexes to enhancer elements located in the ISG promoters. These enhancer elements include the IFN-stimulated response element (ISRE) and the palindromic IFN-γ activation site (GAS) element. Regulated expression of ISRE containing ISG depends on IFN-stimulated gene factor 3 (ISGF3), a heterodimer involving Stat1 and STAT2 in association with a DNA-binding adapter protein, p48/IFN regulatory factor-9 (IRF-9). Several GAS binding Stat complexes involving Stat1, Stat3, Stat4, and Stat5 have been described, but their contribution to GAS-dependent ISG expression remains to be established. We and others previously identified an IFN-α-inducible STAT2:1 heterodimer that exhibits binding to the GAS element of the IRF-1 gene. These previous studies raise the possibility that STAT2:1 may participate in the transcriptional activation of the subset of ISG containi...
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the proximal tyrosines of the cytoplasmic domain of the β chain of the type i interferon receptor are essential for signal transducer and activator of transcription stat 2 activation evidence that two STAT2 sites are required to reach a threshold of
Journal of Biological Chemistry, 1999Co-Authors: Owen W Nadeau, Paul Domanski, Anna Usacheva, Shahab Uddin, Leonidas C Platanias, Paula M Pitha, Regina Raz, David E Levy, Beata Majchrzak, Eleanor N. FishAbstract:The precise role of the different subunits (alpha/IFNAR1 and betaL/IFNAR2) of the type I interferon receptor (IFN-R) in the activation of signal transducer and activator of transcription (Stat) 1, STAT2, and Stat3 has not yet been established. In this report we demonstrate that there are functionally redundant phosphotyrosine-dependent and -independent binding sites for STAT2 in the alpha and beta subunits of the type I IFN-R. Expression of a type I IFN-R containing only the constitutive STAT2 site or the proximal tyrosines of betaL, but not the docking site on the alpha chain (Tyr466 and Tyr481), supported low levels of STAT2 activation. However, the presence of only one intact STAT2 site did not lead to induction of interferon-stimulated gene factor 3 (ISGF3) or an antiviral state. Normal levels of STAT2 tyrosine phosphorylation, induction of ISGF3, and an antiviral effect always required the proximal tyrosines of betaL and at least one of the other STAT2 sites (Tyralpha466, 481 or betaL404-462). These data suggest that a threshold of STAT2 tyrosine phosphorylation is required for complete activation of ISGF3. Interestingly, a receptor in which all tyrosines were mutated to phenylalanine shows normal Stat3 phosphorylation and low levels of activation of Stat1.
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Application of Genomic DNA Affinity Chromatography Identifies Multiple Interferon-α-regulated STAT2 Complexes
Journal of Biological Chemistry, 1996Co-Authors: Julien J. Ghislain, Eleanor N. FishAbstract:Abstract Interferon-α (IFN-α)-induced signal transduction is mediated by the phosphorylation-activation of the signal transducer and activator of transcription (STAT) proteins Stat1, STAT2, and Stat3. Previous studies have shown that these activated STATs dimerize to form four distinct STAT complexes which translocate to the nucleus and activates transcription by binding to specific promoter elements. The interferon-stimulated gene factor-3 (ISGF3) consists of STAT2 and Stat1 heterodimers in association with a DNA-binding protein, p48, that binds to the interferon stimulated response element. Homo- and heterodimers of Stat1 and Stat3 bind to the palindromic interferon response element (pIRE). In this report we demonstrate the utility of a biochemical procedure that we have developed, based on genomic DNA affinity chromatography, for the identification of IFN-α-induced STAT complexes. Using this approach, we identified ISGF3-independent STAT2-containing STAT complexes. Results from the analysis of STAT2 complexes in the electrophoretic mobility shift assay were consistent with genomic DNA affinity chromatography results and identified a STAT2:1 complex that binds with low affinity to the pIRE of the interferon regulatory factor-1 gene. Immunoprecipitation studies of STAT2 revealed an IFN-α dependent co-precipitation of both Stat1 and Stat3. Taken together, our results suggest that IFN-α activates, in addition to ISGF3, other STAT2-containing STAT complexes, one of which binds to an element related to the interferon regulatory factor-1 pIRE.
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Application of Genomic DNA Affinity Chromatography Identifies Multiple Interferon-α-regulated STAT2 Complexes
Journal of Biological Chemistry, 1996Co-Authors: Julien J. Ghislain, Eleanor N. FishAbstract:Abstract Interferon-α (IFN-α)-induced signal transduction is mediated by the phosphorylation-activation of the signal transducer and activator of transcription (STAT) proteins Stat1, STAT2, and Stat3. Previous studies have shown that these activated STATs dimerize to form four distinct STAT complexes which translocate to the nucleus and activates transcription by binding to specific promoter elements. The interferon-stimulated gene factor-3 (ISGF3) consists of STAT2 and Stat1 heterodimers in association with a DNA-binding protein, p48, that binds to the interferon stimulated response element. Homo- and heterodimers of Stat1 and Stat3 bind to the palindromic interferon response element (pIRE). In this report we demonstrate the utility of a biochemical procedure that we have developed, based on genomic DNA affinity chromatography, for the identification of IFN-α-induced STAT complexes. Using this approach, we identified ISGF3-independent STAT2-containing STAT complexes. Results from the analysis of STAT2 complexes in the electrophoretic mobility shift assay were consistent with genomic DNA affinity chromatography results and identified a STAT2:1 complex that binds with low affinity to the pIRE of the interferon regulatory factor-1 gene. Immunoprecipitation studies of STAT2 revealed an IFN-α dependent co-precipitation of both Stat1 and Stat3. Taken together, our results suggest that IFN-α activates, in addition to ISGF3, other STAT2-containing STAT complexes, one of which binds to an element related to the interferon regulatory factor-1 pIRE.
Philippe Plattet - One of the best experts on this subject based on the ideXlab platform.
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two domains of the v protein of virulent canine distemper virus selectively inhibit stat1 and STAT2 nuclear import
Journal of Virology, 2010Co-Authors: Anne Rothlisberger, Dominique Judith Wiener, Matthias Schweizer, Ernst Peterhans, Andreas Zurbriggen, Philippe PlattetAbstract:Canine distemper virus (CDV) causes in dogs a severe systemic infection, with a high frequency of demyelinating encephalitis. Among the six genes transcribed by CDV, the P gene encodes the polymerase cofactor protein (P) as well as two additional nonstructural proteins, C and V; of these V was shown to act as a virulence factor. We investigated the molecular mechanisms by which the P gene products of the neurovirulent CDV A75/17 strain disrupt type I interferon (IFN-α/β)-induced signaling that results in the establishment of the antiviral state. Using recombinant knockout A75/17 viruses, the V protein was identified as the main antagonist of IFN-α/β-mediated signaling. Importantly, immunofluorescence analysis illustrated that the inhibition of IFN-α/β-mediated signaling correlated with impaired STAT1/STAT2 nuclear import, whereas the phosphorylation state of these proteins was not affected. Coimmunoprecipitation assays identified the N-terminal region of V (VNT) responsible for STAT1 targeting, which correlated with its ability to inhibit the activity of the IFN-α/β-mediated antiviral state. Conversely, while the C-terminal domain of V (VCT) could not function autonomously, when fused to VNT it optimally interacted with STAT2 and subsequently efficiently suppressed the IFN-α/β-mediated signaling pathway. The latter result was further supported by a single mutation at position 110 within the VNT domain of CDV V protein, resulting in a mutant that lost STAT1 binding while retaining a partial STAT2 association. Taken together, our results identified the CDV VNT and VCT as two essential modules that complement each other to interfere with the antiviral state induced by IFN-α/β-mediated signaling. Hence, our experiments reveal a novel mechanism of IFN-α/β evasion among the morbilliviruses.
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two domains of the v protein of virulent canine distemper virus selectively inhibit stat1 and STAT2 nuclear import
Journal of Virology, 2010Co-Authors: Anne Rothlisberger, Dominique Judith Wiener, Matthias Schweizer, Ernst Peterhans, Andreas Zurbriggen, Philippe PlattetAbstract:Canine distemper virus (CDV) causes in dogs a severe systemic infection, with a high frequency of demyelinating encephalitis. Among the six genes transcribed by CDV, the P gene encodes the polymerase cofactor protein (P) as well as two additional nonstructural proteins, C and V; of these V was shown to act as a virulence factor. We investigated the molecular mechanisms by which the P gene products of the neurovirulent CDV A75/17 strain disrupt type I interferon (IFN-alpha/beta)-induced signaling that results in the establishment of the antiviral state. Using recombinant knockout A75/17 viruses, the V protein was identified as the main antagonist of IFN-alpha/beta-mediated signaling. Importantly, immunofluorescence analysis illustrated that the inhibition of IFN-alpha/beta-mediated signaling correlated with impaired STAT1/STAT2 nuclear import, whereas the phosphorylation state of these proteins was not affected. Coimmunoprecipitation assays identified the N-terminal region of V (VNT) responsible for STAT1 targeting, which correlated with its ability to inhibit the activity of the IFN-alpha/beta-mediated antiviral state. Conversely, while the C-terminal domain of V (VCT) could not function autonomously, when fused to VNT it optimally interacted with STAT2 and subsequently efficiently suppressed the IFN-alpha/beta-mediated signaling pathway. The latter result was further supported by a single mutation at position 110 within the VNT domain of CDV V protein, resulting in a mutant that lost STAT1 binding while retaining a partial STAT2 association. Taken together, our results identified the CDV VNT and VCT as two essential modules that complement each other to interfere with the antiviral state induced by IFN-alpha/beta-mediated signaling. Hence, our experiments reveal a novel mechanism of IFN-alpha/beta evasion among the morbilliviruses.
Jean Patrick Parisien - One of the best experts on this subject based on the ideXlab platform.
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Composition and assembly of STAT-targeting ubiquitin ligase complexes: paramyxovirus V protein carboxyl terminus is an oligomerization domain.
Journal of Virology, 2005Co-Authors: Christina M. Ulane, Alex Kentsis, Cristian D. Cruz, Jean Patrick Parisien, Kristi L. Schneider, Curt M HorvathAbstract:Transcription regulators STAT1 and STAT2 are key components of the interferon signaling system leading to innate antiviral immunity. The related STAT3 protein is a regulator of interleukin-6-type cytokine signals and can contribute to both cell growth and death important for cancer gene regulation and tumor survival. These three STAT proteins are targeted for proteasome-mediated degradation by RNA viruses in the Rubulavirus genus of the Paramyxoviridae. A single viral protein, the V protein, assembles STAT-specific ubiquitin ligase complexes from cellular components. Simian virus 5 (SV5) targets STAT1, human parainfluenza virus 2 targets STAT2, and mumps virus targets both STAT1 and STAT3. Analysis of the V-dependent degradation complex (VDC) composition and assembly revealed several features contributing to targeting specificity. SV5 and mumps V proteins require STAT2 to recruit the STAT1 target, yet mumps V protein binds STAT3 independent of STAT1 and STAT2. All Rubulavirus V proteins tested require cellular DDB1 to target STATs for degradation but differ in the use of Roc1, which is essential for mumps V STAT3 targeting. Protein interaction analysis reveals that paramyxovirus V proteins can homo- and heterooligomerize and that the conserved cysteine-rich zinc-binding C-terminal domain is necessary and sufficient for oligomerization. Purified SV5 V protein spontaneously assembles into spherical macromolecular particles, and similar particles constitute SV5 and mumps VDC preparations.
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STAT3 ubiquitylation and degradation by mumps virus suppress cytokine and oncogene signaling.
Journal of Virology, 2003Co-Authors: Christina M. Ulane, Jean Patrick Parisien, Jason J. Rodriguez, Curt M HorvathAbstract:Mumps virus is a common infectious agent of humans, causing parotitis, meningitis, encephalitis, and orchitis. Like other paramyxoviruses in the genus Rubulavirus, mumps virus catalyzes the proteasomal degradation of cellular STAT1 protein, a means for escaping antiviral responses initiated by alpha/beta and gamma interferons. We demonstrate that mumps virus also eliminates cellular STAT3, a protein that mediates transcriptional responses to cytokines, growth factors, nonreceptor tyrosine kinases, and a variety of oncogenic stimuli. STAT1 and STAT3 are independently targeted by a single mumps virus protein, called V, that assembles STAT-directed ubiquitylation complexes from cellular components, including STAT1, STAT2, STAT3, DDB1, and Cullin4A. Consequently, mumps virus V protein prevents responses to interleukin-6 and v-Src signals and can induce apoptosis in STAT3-dependent multiple myeloma cells and transformed murine fibroblasts. These findings demonstrate a unique cytokine and oncogene evasion property of mumps virus that provides a molecular basis for its observed oncolytic properties.
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a hybrid irf9 STAT2 protein recapitulates interferon stimulated gene expression and antiviral response
Journal of Biological Chemistry, 2003Co-Authors: Thomas Kraus, Jean Patrick Parisien, Curt M HorvathAbstract:Abstract Type I interferon (IFN) signaling induces the heterotrimeric transcription complex, IFN-stimulated gene factor (ISGF) 3, which contains STAT1, STAT2, and the DNA binding subunit, interferon regulatory factor (IRF) 9. Because IRF9 is targeted to the nucleus in the absence of IFN stimulation, the potential of IRF9 protein for gene regulation was examined using a GAL4 DNA binding domain fusion system. GAL4-IRF9 was transcriptionally active in reporter gene assays but not in the absence of cellular STAT1 and STAT2. However, the inert IRF9 protein was readily converted to a constitutively active ISGF3-like activator by fusion with the C-terminal transcriptional activation domain of STAT2 or the acidic activation domain of herpesvirus VP16. The IRF9 hybrids are targeted to endogenous ISGF3 target loci and can activate their transcription. Moreover, expression of the IRF9-STAT2 fusion can recapitulate the type I IFN biological response, producing a cellular antiviral state that protects cells from virus-induced cytopathic effects and inhibits virus replication. The antiviral state generated by regulated IRF9-STAT2 hybrid protein expression is independent of autocrine IFN signaling and inhibits both RNA and DNA viruses.
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STAT2 acts as a host range determinant for species specific paramyxovirus interferon antagonism and simian virus 5 replication
Journal of Virology, 2002Co-Authors: Jean Patrick Parisien, Curt M HorvathAbstract:The antiviral state induced by alpha/beta interferon (IFN-α/β) is a powerful selective pressure for virus evolution of evasive strategies. The paramyxoviruses simian virus 5 (SV5) and human parainfluenza virus 2 (HPIV2) overcome IFN-α/β responses through the actions of their V proteins, which induce proteasomal degradation of cellular IFN-α/β-activated signal transducers and activators of transcription STAT1 and STAT2. SV5 infection induces STAT1 degradation and IFN-α/β inhibition efficiently in human cells but not in mouse cells, effectively restricting SV5 host range. Here, the cellular basis for this species specificity is demonstrated to result from differences between human and murine STAT2. Expression in mouse cells of full-length or truncated human STAT2 cDNA is sufficient to permit antagonism of endogenous murine IFN-α/β signaling by SV5 and HPIV2 V proteins. Furthermore, virus-induced STAT protein degradation is observed in mouse cells only in the presence of ectopically expressed human STAT2. The results indicate that STAT2 acts as an intracellular determinant of paramyxovirus host range restriction, which contributes to the species specificity of virus replication, and that human STAT2 can confer a growth advantage for SV5 in the murine host.
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selective stat protein degradation induced by paramyxoviruses requires both stat1 and STAT2 but is independent of alpha beta interferon signal transduction
Journal of Virology, 2002Co-Authors: Jean Patrick Parisien, Christina M. Ulane, Jason J. Rodriguez, Curt M HorvathAbstract:The alpha/beta interferon (IFN-α/β)-induced STAT signal transduction pathway leading to activation of the ISGF3 transcription complex and subsequent antiviral responses is the target of viral pathogenesis strategies. Members of the Rubulavirus genus of the Paramyxovirus family of RNA viruses have acquired the ability to specifically target either STAT1 or STAT2 for proteolytic degradation as a countermeasure for evading IFN responses. While type II human parainfluenza virus induces STAT2 degradation, simian virus 5 induces STAT1 degradation. The components of the IFN signaling system that are required for STAT protein degradation by these paramyxoviruses have been investigated in a series of human somatic cell lines deficient in IFN signaling proteins. Results indicate that neither the IFN-α/β receptor, the tyrosine kinases Jak1 or Tyk2, nor the ISGF3 DNA-binding subunit, IFN regulatory factor 9 (IRF9), is required for STAT protein degradation induced by either virus. Nonetheless, both STAT1 and STAT2 are strictly required in the host cell to establish a degradation-permissive environment enabling both viruses to target their respective STAT protein. Complementation studies reveal that STAT protein-activating tyrosine phosphorylation and functional src homology 2 (SH2) domains are dispensable for creating a permissive STAT degradation environment in degradation-incompetent cells, but the N terminus of the missing STAT protein is essential. Protein-protein interaction analysis indicates that V and STAT proteins interact physically in vitro and in vivo. These results constitute genetic and biochemical evidence supporting a virus-induced, IFN-independent STAT protein degradation complex that contains at least STAT1 and STAT2.
Anne Rothlisberger - One of the best experts on this subject based on the ideXlab platform.
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two domains of the v protein of virulent canine distemper virus selectively inhibit stat1 and STAT2 nuclear import
Journal of Virology, 2010Co-Authors: Anne Rothlisberger, Dominique Judith Wiener, Matthias Schweizer, Ernst Peterhans, Andreas Zurbriggen, Philippe PlattetAbstract:Canine distemper virus (CDV) causes in dogs a severe systemic infection, with a high frequency of demyelinating encephalitis. Among the six genes transcribed by CDV, the P gene encodes the polymerase cofactor protein (P) as well as two additional nonstructural proteins, C and V; of these V was shown to act as a virulence factor. We investigated the molecular mechanisms by which the P gene products of the neurovirulent CDV A75/17 strain disrupt type I interferon (IFN-α/β)-induced signaling that results in the establishment of the antiviral state. Using recombinant knockout A75/17 viruses, the V protein was identified as the main antagonist of IFN-α/β-mediated signaling. Importantly, immunofluorescence analysis illustrated that the inhibition of IFN-α/β-mediated signaling correlated with impaired STAT1/STAT2 nuclear import, whereas the phosphorylation state of these proteins was not affected. Coimmunoprecipitation assays identified the N-terminal region of V (VNT) responsible for STAT1 targeting, which correlated with its ability to inhibit the activity of the IFN-α/β-mediated antiviral state. Conversely, while the C-terminal domain of V (VCT) could not function autonomously, when fused to VNT it optimally interacted with STAT2 and subsequently efficiently suppressed the IFN-α/β-mediated signaling pathway. The latter result was further supported by a single mutation at position 110 within the VNT domain of CDV V protein, resulting in a mutant that lost STAT1 binding while retaining a partial STAT2 association. Taken together, our results identified the CDV VNT and VCT as two essential modules that complement each other to interfere with the antiviral state induced by IFN-α/β-mediated signaling. Hence, our experiments reveal a novel mechanism of IFN-α/β evasion among the morbilliviruses.
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two domains of the v protein of virulent canine distemper virus selectively inhibit stat1 and STAT2 nuclear import
Journal of Virology, 2010Co-Authors: Anne Rothlisberger, Dominique Judith Wiener, Matthias Schweizer, Ernst Peterhans, Andreas Zurbriggen, Philippe PlattetAbstract:Canine distemper virus (CDV) causes in dogs a severe systemic infection, with a high frequency of demyelinating encephalitis. Among the six genes transcribed by CDV, the P gene encodes the polymerase cofactor protein (P) as well as two additional nonstructural proteins, C and V; of these V was shown to act as a virulence factor. We investigated the molecular mechanisms by which the P gene products of the neurovirulent CDV A75/17 strain disrupt type I interferon (IFN-alpha/beta)-induced signaling that results in the establishment of the antiviral state. Using recombinant knockout A75/17 viruses, the V protein was identified as the main antagonist of IFN-alpha/beta-mediated signaling. Importantly, immunofluorescence analysis illustrated that the inhibition of IFN-alpha/beta-mediated signaling correlated with impaired STAT1/STAT2 nuclear import, whereas the phosphorylation state of these proteins was not affected. Coimmunoprecipitation assays identified the N-terminal region of V (VNT) responsible for STAT1 targeting, which correlated with its ability to inhibit the activity of the IFN-alpha/beta-mediated antiviral state. Conversely, while the C-terminal domain of V (VCT) could not function autonomously, when fused to VNT it optimally interacted with STAT2 and subsequently efficiently suppressed the IFN-alpha/beta-mediated signaling pathway. The latter result was further supported by a single mutation at position 110 within the VNT domain of CDV V protein, resulting in a mutant that lost STAT1 binding while retaining a partial STAT2 association. Taken together, our results identified the CDV VNT and VCT as two essential modules that complement each other to interfere with the antiviral state induced by IFN-alpha/beta-mediated signaling. Hence, our experiments reveal a novel mechanism of IFN-alpha/beta evasion among the morbilliviruses.
