The Experts below are selected from a list of 45087 Experts worldwide ranked by ideXlab platform
Curt M Horvath - One of the best experts on this subject based on the ideXlab platform.
-
silencing STATs lessons from paramyxovirus interferon evasion
Cytokine & Growth Factor Reviews, 2004Co-Authors: Curt M HorvathAbstract:The signal transducer and activator of transcription (STAT) family Proteins are essential mediators of cytokine and growth factor functions. The interferon (IFN) family of cytokines is well known as modulators of both innate and adaptive anti-microbial immunity. In response to the evolutionary struggle between host and pathogen, many viruses have developed strategies to bypass the IFN antiviral system. Uniquely, the paramyxoviruses have developed the ability to efficiently inactivate STAT Protein function, in many cases using a single virus-encoded Protein called 'V'. The V Protein plays a central role in STAT inhibition, but mechanistic studies have revealed great diversity in V-dependent STAT signaling evasion among paramyxovirus species. These examples of IFN evasion by STAT Protein inactivation can help define targets for antiviral drug design or improving vaccine regimens. Moreover, understanding these STAT inhibition mechanisms are likely to reveal strategic options for the design of STAT-directed therapeutics for treatment of diseases characterized by cytokine hyperactivity.
-
STAT Protein interference and suppression of cytokine signal transduction by measles virus v Protein
Journal of Virology, 2003Co-Authors: Heidi Palosaari, Jean Patrick Parisien, Christina M. Ulane, Jason J. Rodriguez, Curt M HorvathAbstract:Measles virus, a paramyxovirus of the Morbillivirus genus, is responsible for an acute childhood illness that infects over 40 million people and leads to the deaths of more than 1 million people annually (C. J. Murray and A. D. Lopez, Lancet 349:1269-1276, 1997). Measles virus infection is characterized by virus-induced immune suppression that creates susceptibility to opportunistic infections. Here we demonstrate that measles virus can inhibit cytokine responses by direct interference with host STAT Protein-dependent signaling systems. Expression of the measles V Protein prevents alpha, beta, and gamma interferon-induced transcriptional responses. Furthermore, it can interfere with signaling by interleukin-6 and the non-receptor tyrosine kinase, v-Src. Affinity purification demonstrates that the measles V Protein associates with cellular STAT1, STAT2, STAT3, and IRF9, as well as several unidentified partners. Mechanistic studies indicate that while the measles V Protein does not interfere with STAT1 or STAT2 tyrosine phosphorylation, it causes a defect in IFN-induced STAT nuclear accumulation. The defective STAT nuclear redistribution is also observed in measles virus-infected cells, where some of the STAT Protein is detected in cytoplasmic bodies that contain viral nucleocapsid Protein and nucleic acids. Interference with STAT-inducible transcription may provide a novel intracellular mechanism for measles virus-induced cytokine inhibition that links innate immune evasion to adaptive immune suppression.
-
Paramyxoviruses SV5 and HPIV2 assemble STAT Protein ubiquitin ligase complexes from cellular components.
Virology, 2002Co-Authors: Christina M. Ulane, Curt M HorvathAbstract:Signal transducer and activator of transcription (STAT) Proteins are normally long-lived, but infection with certain Paramyxoviruses results in efficient loss of IFN-responsive STAT1 or STAT2. Expression of a virus-encoded Protein called "V" is sufficient to mediate the destruction of STAT Proteins. STAT degradation is blocked by proteasome inhibitors, strongly implicating the ubiquitin (Ub)-proteasome targeting system. We demonstrate that cellular expression of V Proteins from simian virus 5 (SV5) and type II human parainfluenza virus (HPIV2) induces polyubiquitylation of STAT1 and STAT2 targets. In vitro, the V Proteins catalyze Ub transfer in an ATP-dependent process that requires both Ub-activating (E1) and Ub-conjugating (E2) activities. Furthermore, SV5 and HPIV2 V-interacting Protein partners were isolated by affinity purification from human cells and reveal a complex of associated cellular Proteins. This complex includes both STAT1 and STAT2, and the damaged DNA binding Protein, DDB1. In addition, a Protein related to a family of cellular Ub ligase complex subunits, cullin 4A (Cul4A), associated with the V Proteins. The roles of both DDB1 and Cul4A in STAT1 degradation by SV5 infection were analyzed using small interfering RNAs. These findings demonstrate the assembly of a V-dependent degradation complex that includes STAT1, STAT2, DDB1, and Cul4A. In agreement with prior nomenclature on SCF-type cellular E3 enzymes, we refer to this complex as VDC.
-
nipah virus v Protein evades alpha and gamma interferons by preventing STAT1 and STAT2 activation and nuclear accumulation
Journal of Virology, 2002Co-Authors: Jason J. Rodriguez, Jean Patrick Parisien, Curt M HorvathAbstract:Characterization of recent outbreaks of fatal encephalitis in southeast Asia identified the causative agent to be a previously unrecognized enveloped negative-strand RNA virus of the Paramyxoviridae family, Nipah virus. One feature linking Nipah virus to this family is a conserved cysteine-rich domain that is the hallmark of paramyxovirus V Proteins. The V Proteins of other paramyxovirus species have been linked with evasion of host cell interferon (IFN) signal transduction and subsequent antiviral responses by inducing proteasomal degradation of the IFN-responsive transcription factors, STAT1 or STAT2. Here we demonstrate that Nipah virus V Protein escapes IFN by a distinct mechanism involving direct inhibition of STAT Protein function. Nipah virus V Protein differs from other paramyxovirus V Proteins in its subcellular distribution but not in its ability to inhibit cellular IFN responses. Nipah virus V Protein does not induce STAT degradation but instead inhibits IFN responses by forming high-molecular-weight complexes with both STAT1 and STAT2. We demonstrate that Nipah virus V Protein accumulates in the cytoplasm by a Crm1-dependent mechanism, alters the STAT Protein subcellular distribution in the steady STATe, and prevents IFN-stimulated STAT redistribution. Consistent with the formation of complexes, STAT Protein tyrosine phosphorylation is inhibited in cells expressing the Nipah virus V Protein. As a result, Nipah virus V Protein efficiently prevents STAT1 and STAT2 nuclear translocation in response to IFN, inhibiting cellular responses to both IFN-α and IFN-γ.
-
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.
Warren J Leonard - One of the best experts on this subject based on the ideXlab platform.
-
analysis of γc family cytokine target genes identification of dual specificity phosphatase 5 dusp5 as a regulator of mitogen activated Protein kinase activity in interleukin 2 signaling
Journal of Biological Chemistry, 2003Co-Authors: Panu E Kovanen, Jacqueline Fu, Elaine M Hurt, Jennifer M. Giltnane, Louis M Staudt, George E. Wright, Andreas Rosenwald, Warren J LeonardAbstract:Abstract Interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21 form a family of cytokines based on their sharing the common cytokine receptor γ chain, γc, which is mutated in X-linked severe combined immunodeficiency (SCID). As a step toward further elucidating the mechanism of action of these cytokines in T-cell biology, we compared the gene expression profiles of IL-2, IL-4, IL-7, and IL-15 in T cells using cDNA microarrays. IL-2, IL-7, and IL-15 each induced a highly similar set of genes, whereas IL-4 induced distinct genes correlating with differential STAT Protein activation by this cytokine. One gene induced by IL-2, IL-7, and IL-15 but not IL-4 was dual-specificity phosphatase 5 (DUSP5). In IL-2-dependent CTLL-2 cells, we show that IL-2-induced ERK-1/2 activity was inhibited by wild type DUSP5 but markedly increased by an inactive form of DUSP5, suggesting a negative feedback role for DUSP5 in IL-2 signaling. Our findings provide insights into the shared versus distinctive actions by different members of the γc family of cytokines. Moreover, we have identified a DUSP5-dependent negative regulatory pathway for MAPK activity in T cells.
-
analysis of gamma c family cytokine target genes identification of dual specificity phosphatase 5 dusp5 as a regulator of mitogen activated Protein kinase activity in interleukin 2 signaling
Journal of Biological Chemistry, 2003Co-Authors: Panu E Kovanen, Elaine M Hurt, Jennifer M. Giltnane, Louis M Staudt, George E. Wright, Andreas Rosenwald, Lloyd T Lam, Warren J LeonardAbstract:Interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21 form a family of cytokines based on their sharing the common cytokine receptor gamma chain, gamma(c), which is mutated in X-linked severe combined immunodeficiency (SCID). As a step toward further elucidating the mechanism of action of these cytokines in T-cell biology, we compared the gene expression profiles of IL-2, IL-4, IL-7, and IL-15 in T cells using cDNA microarrays. IL-2, IL-7, and IL-15 each induced a highly similar set of genes, whereas IL-4 induced distinct genes correlating with differential STAT Protein activation by this cytokine. One gene induced by IL-2, IL-7, and IL-15 but not IL-4 was dual-specificity phosphatase 5 (DUSP5). In IL-2-dependent CTLL-2 cells, we show that IL-2-induced ERK-1/2 activity was inhibited by wild type DUSP5 but markedly increased by an inactive form of DUSP5, suggesting a negative feedback role for DUSP5 in IL-2 signaling. Our findings provide insights into the shared versus distinctive actions by different members of the gamma(c) family of cytokines. Moreover, we have identified a DUSP5-dependent negative regulatory pathway for MAPK activity in T cells.
Panu E Kovanen - One of the best experts on this subject based on the ideXlab platform.
-
analysis of γc family cytokine target genes identification of dual specificity phosphatase 5 dusp5 as a regulator of mitogen activated Protein kinase activity in interleukin 2 signaling
Journal of Biological Chemistry, 2003Co-Authors: Panu E Kovanen, Jacqueline Fu, Elaine M Hurt, Jennifer M. Giltnane, Louis M Staudt, George E. Wright, Andreas Rosenwald, Warren J LeonardAbstract:Abstract Interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21 form a family of cytokines based on their sharing the common cytokine receptor γ chain, γc, which is mutated in X-linked severe combined immunodeficiency (SCID). As a step toward further elucidating the mechanism of action of these cytokines in T-cell biology, we compared the gene expression profiles of IL-2, IL-4, IL-7, and IL-15 in T cells using cDNA microarrays. IL-2, IL-7, and IL-15 each induced a highly similar set of genes, whereas IL-4 induced distinct genes correlating with differential STAT Protein activation by this cytokine. One gene induced by IL-2, IL-7, and IL-15 but not IL-4 was dual-specificity phosphatase 5 (DUSP5). In IL-2-dependent CTLL-2 cells, we show that IL-2-induced ERK-1/2 activity was inhibited by wild type DUSP5 but markedly increased by an inactive form of DUSP5, suggesting a negative feedback role for DUSP5 in IL-2 signaling. Our findings provide insights into the shared versus distinctive actions by different members of the γc family of cytokines. Moreover, we have identified a DUSP5-dependent negative regulatory pathway for MAPK activity in T cells.
-
analysis of gamma c family cytokine target genes identification of dual specificity phosphatase 5 dusp5 as a regulator of mitogen activated Protein kinase activity in interleukin 2 signaling
Journal of Biological Chemistry, 2003Co-Authors: Panu E Kovanen, Elaine M Hurt, Jennifer M. Giltnane, Louis M Staudt, George E. Wright, Andreas Rosenwald, Lloyd T Lam, Warren J LeonardAbstract:Interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21 form a family of cytokines based on their sharing the common cytokine receptor gamma chain, gamma(c), which is mutated in X-linked severe combined immunodeficiency (SCID). As a step toward further elucidating the mechanism of action of these cytokines in T-cell biology, we compared the gene expression profiles of IL-2, IL-4, IL-7, and IL-15 in T cells using cDNA microarrays. IL-2, IL-7, and IL-15 each induced a highly similar set of genes, whereas IL-4 induced distinct genes correlating with differential STAT Protein activation by this cytokine. One gene induced by IL-2, IL-7, and IL-15 but not IL-4 was dual-specificity phosphatase 5 (DUSP5). In IL-2-dependent CTLL-2 cells, we show that IL-2-induced ERK-1/2 activity was inhibited by wild type DUSP5 but markedly increased by an inactive form of DUSP5, suggesting a negative feedback role for DUSP5 in IL-2 signaling. Our findings provide insights into the shared versus distinctive actions by different members of the gamma(c) family of cytokines. Moreover, we have identified a DUSP5-dependent negative regulatory pathway for MAPK activity in T cells.
Nadia Zaffaroni - One of the best experts on this subject based on the ideXlab platform.
-
Lack of p21waf1 and p27kip1 Protein induction by interferon-alpha2a in human melanoma cell lines.
Melanoma Research, 1999Co-Authors: A Bearzatto, L Orlandi, De Marco C, Daidone Mg, Nadia ZaffaroniAbstract:The ability of human recombinant interferon-alpha2a (IFNalpha2a) to induce the expression of cyclin-dependent kinase inhibitors p21waf1 and p27kip1 consequent to signal transducers and activators of transcription (STAT) Protein activation was investigated in six human melanoma cell lines with different susceptibilities to the antiproliferative effect of the cytokine. All the cell lines expressed IFNalpha and IFNalpha/beta receptors. Exposure for 24 h to IFNalpha2a markedly enhanced the nuclear expression of STAT1 and STAT2 Proteins in all the cell lines. However, no induction of p21waf1 or p27kip1 was consistently observed. Overall, results from the study suggest that the induction of such cyclin-dependent kinase inhibitors is not a major mechanism for the antiproliferative effect of IFNalpha2a, at least in human melanoma cell lines.
-
combined effects of interferon alpha2a and 13 cis retinoic acid on human melanoma cell growth and STAT Protein expression
Melanoma Research, 1998Co-Authors: A Bearzatto, L Orlandi, Rosella Silvestrini, F Belli, N Cascinelli, Nadia ZaffaroniAbstract:We assessed the antiproliferative effects of human recombinant interferon-alpha2a (IFNalpha2a) and 13-cis-retinoic acid (13cis-RA) on two human melanoma cell lines (JR8 and M14). Both cell lines showed a very modest sensitivity to IFNalpha2a and 13cis-RA as single agents. In JR8 cells, the combination of the two compounds consistently produced simple additive effects. In contrast, different effects of the combination were recorded in the M14 cell line depending on the treatment schedule. Specifically, an additive interaction was observed when IFNalpha2a and 13cis-RA were given in sequence, independently of the order of drug administration, whereas a supra-additive antiproliferative effect was seen when cells were simultaneously exposed to the two drugs. Exposure to 1000 IU/ml IFNalpha2a markedly increased the nuclear expression of signal transducers and activators of transcription (STAT) Proteins in both cell lines. By itself 10 microM 13cis-RA did not affect STAT Protein expression or modify the extent of activation of such Proteins by IFNalpha2a. Results from our study showed an enhancement of the antiproliferative activity of IFNalpha2a and 13cis-RA when given in combination and suggest that such an enhancement is not mediated by a concomitant effect of 13cis-RA on STAT Protein activation.
Jean Patrick Parisien - One of the best experts on this subject based on the ideXlab platform.
-
STAT Protein interference and suppression of cytokine signal transduction by measles virus v Protein
Journal of Virology, 2003Co-Authors: Heidi Palosaari, Jean Patrick Parisien, Christina M. Ulane, Jason J. Rodriguez, Curt M HorvathAbstract:Measles virus, a paramyxovirus of the Morbillivirus genus, is responsible for an acute childhood illness that infects over 40 million people and leads to the deaths of more than 1 million people annually (C. J. Murray and A. D. Lopez, Lancet 349:1269-1276, 1997). Measles virus infection is characterized by virus-induced immune suppression that creates susceptibility to opportunistic infections. Here we demonstrate that measles virus can inhibit cytokine responses by direct interference with host STAT Protein-dependent signaling systems. Expression of the measles V Protein prevents alpha, beta, and gamma interferon-induced transcriptional responses. Furthermore, it can interfere with signaling by interleukin-6 and the non-receptor tyrosine kinase, v-Src. Affinity purification demonstrates that the measles V Protein associates with cellular STAT1, STAT2, STAT3, and IRF9, as well as several unidentified partners. Mechanistic studies indicate that while the measles V Protein does not interfere with STAT1 or STAT2 tyrosine phosphorylation, it causes a defect in IFN-induced STAT nuclear accumulation. The defective STAT nuclear redistribution is also observed in measles virus-infected cells, where some of the STAT Protein is detected in cytoplasmic bodies that contain viral nucleocapsid Protein and nucleic acids. Interference with STAT-inducible transcription may provide a novel intracellular mechanism for measles virus-induced cytokine inhibition that links innate immune evasion to adaptive immune suppression.
-
nipah virus v Protein evades alpha and gamma interferons by preventing STAT1 and STAT2 activation and nuclear accumulation
Journal of Virology, 2002Co-Authors: Jason J. Rodriguez, Jean Patrick Parisien, Curt M HorvathAbstract:Characterization of recent outbreaks of fatal encephalitis in southeast Asia identified the causative agent to be a previously unrecognized enveloped negative-strand RNA virus of the Paramyxoviridae family, Nipah virus. One feature linking Nipah virus to this family is a conserved cysteine-rich domain that is the hallmark of paramyxovirus V Proteins. The V Proteins of other paramyxovirus species have been linked with evasion of host cell interferon (IFN) signal transduction and subsequent antiviral responses by inducing proteasomal degradation of the IFN-responsive transcription factors, STAT1 or STAT2. Here we demonstrate that Nipah virus V Protein escapes IFN by a distinct mechanism involving direct inhibition of STAT Protein function. Nipah virus V Protein differs from other paramyxovirus V Proteins in its subcellular distribution but not in its ability to inhibit cellular IFN responses. Nipah virus V Protein does not induce STAT degradation but instead inhibits IFN responses by forming high-molecular-weight complexes with both STAT1 and STAT2. We demonstrate that Nipah virus V Protein accumulates in the cytoplasm by a Crm1-dependent mechanism, alters the STAT Protein subcellular distribution in the steady STATe, and prevents IFN-stimulated STAT redistribution. Consistent with the formation of complexes, STAT Protein tyrosine phosphorylation is inhibited in cells expressing the Nipah virus V Protein. As a result, Nipah virus V Protein efficiently prevents STAT1 and STAT2 nuclear translocation in response to IFN, inhibiting cellular responses to both IFN-α and IFN-γ.
-
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.
-
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.
-
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, Joe F Lau, Curt M HorvathAbstract:The alpha/beta interferon (IFN-alpha/beta)-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-alpha/beta 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.