stat2 transcription factor

Summary

Summary: A signal transducer and activator of transcription that mediates cellular responses to TYPE I INTERFERONS. Stat2 protein is associated constitutively with INTERFERON REGULATORY FACTOR-9. After PHOSPHORYLATION Stat2 forms the IFN-STIMULATED GENE FACTOR 3 COMPLEX to regulate expression of target GENES.

Top Publications

  1. Christian S, Collier T, Zu D, Licursi M, Hough C, Hirasawa K. Activated Ras/MEK inhibits the antiviral response of alpha interferon by reducing STAT2 levels. J Virol. 2009;83:6717-26 pubmed publisher
    ..Thus, the activation of the Ras/MEK pathway reduces the amount of STAT2 available for propagating the IFN signal, resulting in the impairment of the IFN-alpha-induced antiviral response. ..
  2. Persky M, Murphy K, Farrar J. IL-12, but not IFN-alpha, promotes STAT4 activation and Th1 development in murine CD4+ T cells expressing a chimeric murine/human Stat2 gene. J Immunol. 2005;174:294-301 pubmed
  3. Li X, Leung S, Kerr I, Stark G. Functional subdomains of STAT2 required for preassociation with the alpha interferon receptor and for signaling. Mol Cell Biol. 1997;17:2048-56 pubmed
    ..Upon activation, the IFNAR1 subunit is phosphorylated on Tyr-466, allowing the SH2 domain of STAT2 to bind to it; this is followed by the sequential phosphorylation of STAT2 and STAT1. ..
  4. Best S, Morris K, Shannon J, Robertson S, Mitzel D, Park G, et al. Inhibition of interferon-stimulated JAK-STAT signaling by a tick-borne flavivirus and identification of NS5 as an interferon antagonist. J Virol. 2005;79:12828-39 pubmed
    ..Because NS5 may interfere with both innate and acquired immune responses to virus infection, this protein may have a significant role in viral pathogenesis. ..
  5. Ramaswamy M, Shi L, Monick M, Hunninghake G, Look D. Specific inhibition of type I interferon signal transduction by respiratory syncytial virus. Am J Respir Cell Mol Biol. 2004;30:893-900 pubmed
    ..Decreased antiviral gene expression in RSV-infected airway epithelial cells may allow RSV replication and establishment of a productive viral infection through subversion of IFN-dependent immunity. ..
  6. Umareddy I, Tang K, Vasudevan S, Devi S, Hibberd M, Gu F. Dengue virus regulates type I interferon signalling in a strain-dependent manner in human cell lines. J Gen Virol. 2008;89:3052-62 pubmed publisher
    ..Our report indicates the existence of a strain-specific virulence factor that may impact on disease severity. ..
  7. Ramaswamy M, Shi L, Varga S, Barik S, Behlke M, Look D. Respiratory syncytial virus nonstructural protein 2 specifically inhibits type I interferon signal transduction. Virology. 2006;344:328-39 pubmed
    ..Taken together, our results indicate that NS2 regulates Stat2 levels during RSV infection, thereby modulating viral effects on interferon-dependent gene expression. ..
  8. Melen K, Keskinen P, Lehtonen A, Julkunen I. Interferon-induced gene expression and signaling in human hepatoma cell lines. J Hepatol. 2000;33:764-72 pubmed
    ..The results indicate positive feedback mechanisms in the IFN signaling system in hepatoma cells. ..
  9. Sarkis P, Ying S, Xu R, Yu X. STAT1-independent cell type-specific regulation of antiviral APOBEC3G by IFN-alpha. J Immunol. 2006;177:4530-40 pubmed
    ..However, STAT1 signaling was functional and required for IFN-gamma induction of A3G in these cells. Our results indicate that A3G may participate in antiviral cellular defenses through a novel IFN-mediated signaling pathway. ..

More Information

Publications62

  1. Rosas Murrieta N, Herrera Camacho I, Vallejo Ruiz V, Millán Pérez Peña L, Cruz C, Tapia Ramírez J, et al. Differential sensitivity to interferon influences the replication and transcription of Urabe AM9 mumps virus variants in nerve cells. Microbes Infect. 2007;9:864-72 pubmed
    ..Our results suggest that the replication efficiency of Urabe AM9 mumps virus variants is influenced by their sensitivity to interferon and their capacity to reduce the antiviral response. ..
  2. Tang X, Gao J, Guan Y, McLane K, Yuan Z, Ramratnam B, et al. Acetylation-dependent signal transduction for type I interferon receptor. Cell. 2007;131:93-105 pubmed
    ..These results have significant implications concerning the central role of acetylation in cytokine receptor signal transduction. ..
  3. Jones M, Davidson A, Hibbert L, Gruenwald P, Schlaak J, Ball S, et al. Dengue virus inhibits alpha interferon signaling by reducing STAT2 expression. J Virol. 2005;79:5414-20 pubmed
    ..Collectively, these data show that dengue virus is capable of subverting the human IFN response by down-regulating STAT2 expression. ..
  4. Hahm B, Trifilo M, Zuniga E, Oldstone M. Viruses evade the immune system through type I interferon-mediated STAT2-dependent, but STAT1-independent, signaling. Immunity. 2005;22:247-57 pubmed
    ..These observations have implications for understanding and developing therapies to treat diseases caused by immunosuppression and/or persistent infections. ..
  5. Rodriguez J, Wang L, Horvath C. Hendra virus V protein inhibits interferon signaling by preventing STAT1 and STAT2 nuclear accumulation. J Virol. 2003;77:11842-5 pubmed
    ..These findings demonstrate a V protein-mediated IFN signal evasion mechanism that is a general property of the known Henipavirus species. ..
  6. Ulane C, Horvath C. Paramyxoviruses SV5 and HPIV2 assemble STAT protein ubiquitin ligase complexes from cellular components. Virology. 2002;304:160-6 pubmed
    ..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. ..
  7. Andrejeva J, Poole E, Young D, Goodbourn S, Randall R. The p127 subunit (DDB1) of the UV-DNA damage repair binding protein is essential for the targeted degradation of STAT1 by the V protein of the paramyxovirus simian virus 5. J Virol. 2002;76:11379-86 pubmed
    ..These results suggest that DDB1, STAT1, STAT2, and V may form part of a large multiprotein complex which leads to the targeted degradation of STAT1 by the proteasome. ..
  8. Cheon H, Holvey Bates E, Schoggins J, Forster S, Hertzog P, Imanaka N, et al. IFN?-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage. EMBO J. 2013;32:2751-63 pubmed publisher
  9. Kraus T, Garza L, Horvath C. Enabled interferon signaling evasion in an immune-competent transgenic mouse model of parainfluenza virus 5 infection. Virology. 2008;371:196-205 pubmed
    ..These transgenic mice provide a small animal model to study the role of innate immune evasion in paramyxovirus pathogenesis. ..
  10. Caignard G, Bouraï M, Jacob Y, Tangy F, Vidalain P. Inhibition of IFN-alpha/beta signaling by two discrete peptides within measles virus V protein that specifically bind STAT1 and STAT2. Virology. 2009;383:112-20 pubmed publisher
    ..Altogether, our results illustrate how a single viral protein has evolved to achieve a robust inhibition of the antiviral response by interacting with several signaling molecules. ..
  11. Paulson M, Pisharody S, Pan L, Guadagno S, Mui A, Levy D. Stat protein transactivation domains recruit p300/CBP through widely divergent sequences. J Biol Chem. 1999;274:25343-9 pubmed
    ..These data demonstrate that highly diverged primary sequences can serve similar or identical functions, and that the minimal regions of similarity between human and mouse Stat2 may define the critical determinants for function. ..
  12. Radaeva S, Jaruga B, Hong F, Kim W, Fan S, Cai H, et al. Interferon-alpha activates multiple STAT signals and down-regulates c-Met in primary human hepatocytes. Gastroenterology. 2002;122:1020-34 pubmed
    ..IFN-alpha directly targets human hepatocytes, followed by activation of multiple STATs and regulation of a wide variety of genes, which may contribute to the antiviral and antitumor activities of IFN-alpha in human liver. ..
  13. Zimmermann A, Trilling M, Wagner M, Wilborn M, Bubic I, Jonjic S, et al. A cytomegaloviral protein reveals a dual role for STAT2 in IFN-{gamma} signaling and antiviral responses. J Exp Med. 2005;201:1543-53 pubmed
    ..pM27 represents a new strategy for simultaneous evasions from types I and II IFNs, and it documents an unknown biological significance for STAT2 in antiviral IFN-gamma responses. ..
  14. Kato A, Cortese Grogan C, Moyer S, Sugahara F, Sakaguchi T, Kubota T, et al. Characterization of the amino acid residues of sendai virus C protein that are critically involved in its interferon antagonism and RNA synthesis down-regulation. J Virol. 2004;78:7443-54 pubmed
    ..Thus, amino acid sequence requirements differ greatly between IFN antagonism and RNA synthesis inhibition. In addition, we confirmed that another SeV accessory protein, V, does not antagonize IFN. ..
  15. Ashour J, Laurent Rolle M, Shi P, Garcia Sastre A. NS5 of dengue virus mediates STAT2 binding and degradation. J Virol. 2009;83:5408-18 pubmed publisher
    ..Therefore, we have identified both a novel mechanism by which DENV evades the innate immune response and a potential target for antiviral therapeutics. ..
  16. Yokota S, Saito H, Kubota T, Yokosawa N, Amano K, Fujii N. Measles virus suppresses interferon-alpha signaling pathway: suppression of Jak1 phosphorylation and association of viral accessory proteins, C and V, with interferon-alpha receptor complex. Virology. 2003;306:135-46 pubmed
    ..Our data suggest that functional disorder of the type I IFN receptor complex is due to "freezing" of the receptor through its association with the C and/or V proteins of MeV. ..
  17. Wacher C, Müller M, Hofer M, Getts D, Zabaras R, Ousman S, et al. Coordinated regulation and widespread cellular expression of interferon-stimulated genes (ISG) ISG-49, ISG-54, and ISG-56 in the central nervous system after infection with distinct viruses. J Virol. 2007;81:860-71 pubmed
    ..These findings suggest a dominant role for the ISG-49, ISG-54, and ISG-56 genes in the host response to different viruses in the central nervous system, where, particularly in neurons, these genes may have nonredundant functions. ..
  18. Hazari S, Taylor L, Haque S, Garry R, Florman S, Luftig R, et al. Reduced expression of Jak-1 and Tyk-2 proteins leads to interferon resistance in hepatitis C virus replicon. Virol J. 2007;4:89 pubmed
    ..This in vitro study provides evidence that altered expression of the Jak-Stat signaling proteins can cause IFN resistance using HCV replicon cell clones. ..
  19. Farrar J, Smith J, Murphy T, Leung S, Stark G, Murphy K. Selective loss of type I interferon-induced STAT4 activation caused by a minisatellite insertion in mouse Stat2. Nat Immunol. 2000;1:65-9 pubmed
    ..This defect in murine Stat2 suggests that the signals leading to STAT4 activation and TH1 development in CD4+ T cells are different between mice and humans. ..
  20. Martinez Moczygemba M, Gutch M, French D, Reich N. Distinct STAT structure promotes interaction of STAT2 with the p48 subunit of the interferon-alpha-stimulated transcription factor ISGF3. J Biol Chem. 1997;272:20070-6 pubmed
    ..p48 complex and a distinct STAT2.STAT1 complex after IFN-alpha stimulation. Data suggest that distinct bipartite complexes STAT2.p48 and STAT2.STAT1 translocate to the nucleus and associate on the DNA target site as ISGF3. ..
  21. Banninger G, Reich N. STAT2 nuclear trafficking. J Biol Chem. 2004;279:39199-206 pubmed
    ..The regulation of STAT2 nuclear trafficking is distinct from the previously characterized STAT1 factor. ..
  22. Park C, Li S, Cha E, Schindler C. Immune response in Stat2 knockout mice. Immunity. 2000;13:795-804 pubmed
    ..Intriguingly, Stat2-deficient fibroblasts exhibit a more significant defect in their response to type I IFNs than macrophages, highlighting tissue-specific differences in the response to this family of ligands. ..
  23. Lou Y, Pan X, Jia P, Li D, Xiao S, Zhang Z, et al. IRF-9/STAT2 [corrected] functional interaction drives retinoic acid-induced gene G expression independently of STAT1. Cancer Res. 2009;69:3673-80 pubmed publisher
  24. Brierley M, Marchington K, Jurisica I, Fish E. Identification of GAS-dependent interferon-sensitive target genes whose transcription is STAT2-dependent but ISGF3-independent. FEBS J. 2006;273:1569-81 pubmed
    ..This report is the first analysis of the contribution of the STAT2 DNA binding domain to IFN responses on a global basis, and shows that STAT2 is required for the IFN-inducible activation of the full spectrum of GAS target genes. ..
  25. Ulane C, Kentsis A, Cruz C, Parisien J, Schneider K, Horvath C. Composition and assembly of STAT-targeting ubiquitin ligase complexes: paramyxovirus V protein carboxyl terminus is an oligomerization domain. J Virol. 2005;79:10180-9 pubmed
    ..Purified SV5 V protein spontaneously assembles into spherical macromolecular particles, and similar particles constitute SV5 and mumps VDC preparations. ..
  26. Precious B, Young D, Andrejeva L, Goodbourn S, Randall R. In vitro and in vivo specificity of ubiquitination and degradation of STAT1 and STAT2 by the V proteins of the paramyxoviruses simian virus 5 and human parainfluenza virus type 2. J Gen Virol. 2005;86:151-8 pubmed
    ..Thus, the V protein of SV5 appears to be highly specific for STAT1 degradation, but the V protein of hPIV2 is more promiscuous. ..
  27. Colamonici O, Yan H, Domanski P, Handa R, Smalley D, Mullersman J, et al. Direct binding to and tyrosine phosphorylation of the alpha subunit of the type I interferon receptor by p135tyk2 tyrosine kinase. Mol Cell Biol. 1994;14:8133-42 pubmed
    ..These data support the hypothesis that the Tyk2 protein functions as part of a receptor complex to initiate intracellular signaling in response to type I IFNs. ..
  28. Fagerlund R, Melen K, Kinnunen L, Julkunen I. Arginine/lysine-rich nuclear localization signals mediate interactions between dimeric STATs and importin alpha 5. J Biol Chem. 2002;277:30072-8 pubmed
    ..Our results demonstrate that specific NLSs in STATs mediate direct interactions of STAT dimers with importin alpha, which activates the nuclear import process. ..
  29. Yan H, Krishnan K, Greenlund A, Gupta S, Lim J, Schreiber R, et al. Phosphorylated interferon-alpha receptor 1 subunit (IFNaR1) acts as a docking site for the latent form of the 113 kDa STAT2 protein. EMBO J. 1996;15:1064-74 pubmed
    ..These observations are consistent with a model in which IFNaR1 mediates the interaction between JAK kinases and the STAT transcription factors. ..
  30. Lo M, Brazas R, Holtzman M. Respiratory syncytial virus nonstructural proteins NS1 and NS2 mediate inhibition of Stat2 expression and alpha/beta interferon responsiveness. J Virol. 2005;79:9315-9 pubmed
    ..RSV infection decreased human but not mouse Stat2 levels, so this mechanism of IFN antagonism may contribute to viral host range, as well as immune subversion. ..
  31. Sakamoto S, Potla R, Larner A. Histone deacetylase activity is required to recruit RNA polymerase II to the promoters of selected interferon-stimulated early response genes. J Biol Chem. 2004;279:40362-7 pubmed
    ..This particular function of IRF9 requires the activity of histone deacetylases. ..
  32. Rodriguez J, Cruz C, Horvath C. Identification of the nuclear export signal and STAT-binding domains of the Nipah virus V protein reveals mechanisms underlying interferon evasion. J Virol. 2004;78:5358-67 pubmed
    ..These findings characterize essential regions for Henipavirus V proteins that represent potential targets for therapeutic intervention. ..
  33. Gotoh B, Takeuchi K, Komatsu T, Yokoo J. The STAT2 activation process is a crucial target of Sendai virus C protein for the blockade of alpha interferon signaling. J Virol. 2003;77:3360-70 pubmed
    ..Furthermore, expression of STAT1 enhanced the inhibitory effect of the C protein on STAT2 activation in U3A cells. The C protein thus appears to participate in the inhibitory process for STAT2 activation through the STAT1 interaction. ..
  34. Rodriguez J, Parisien J, Horvath C. Nipah virus V protein evades alpha and gamma interferons by preventing STAT1 and STAT2 activation and nuclear accumulation. J Virol. 2002;76:11476-83 pubmed
    ..As a result, Nipah virus V protein efficiently prevents STAT1 and STAT2 nuclear translocation in response to IFN, inhibiting cellular responses to both IFN-alpha and IFN-gamma. ..
  35. Parisien J, Lau J, Horvath C. STAT2 acts as a host range determinant for species-specific paramyxovirus interferon antagonism and simian virus 5 replication. J Virol. 2002;76:6435-41 pubmed
  36. Wang J, Pham Mitchell N, Schindler C, Campbell I. Dysregulated Sonic hedgehog signaling and medulloblastoma consequent to IFN-alpha-stimulated STAT2-independent production of IFN-gamma in the brain. J Clin Invest. 2003;112:535-43 pubmed
    ..Moreover, a hitherto unknown role is indicated for the immune system in the pathogenesis of developmental disorders and tumorigenesis of the CNS via dysregulated Shh signaling mediated by IFN-gamma. ..
  37. Lin W, Choe W, Hiasa Y, Kamegaya Y, Blackard J, Schmidt E, et al. Hepatitis C virus expression suppresses interferon signaling by degrading STAT1. Gastroenterology. 2005;128:1034-41 pubmed
    ..STAT1 plays an indispensable role in innate antiviral immunity against HCV expression. In turn, HCV subverts the Jak-STAT kinase by selectively inducing STAT1 degradation. ..
  38. Andrejeva J, Young D, Goodbourn S, Randall R. Degradation of STAT1 and STAT2 by the V proteins of simian virus 5 and human parainfluenza virus type 2, respectively: consequences for virus replication in the presence of alpha/beta and gamma interferons. J Virol. 2002;76:2159-67 pubmed
    ..The significance of the results in terms of the strategy that these viruses have evolved to circumvent the IFN response is discussed. ..
  39. Bluyssen H, Levy D. Stat2 is a transcriptional activator that requires sequence-specific contacts provided by stat1 and p48 for stable interaction with DNA. J Biol Chem. 1997;272:4600-5 pubmed
  40. Park C, Lecomte M, Schindler C. Murine Stat2 is uncharacteristically divergent. Nucleic Acids Res. 1999;27:4191-9 pubmed
    ..To explore this possibility, proteins that interact with the C-termini of murine and human Stat2 were examined. These studies indicate that the murine and human C-termini interact with an overlapping, but distinct set of proteins. ..
  41. Parisien J, Lau J, Rodriguez J, Ulane C, Horvath C. Selective STAT protein degradation induced by paramyxoviruses requires both STAT1 and STAT2 but is independent of alpha/beta interferon signal transduction. J Virol. 2002;76:4190-8 pubmed
    ..These results constitute genetic and biochemical evidence supporting a virus-induced, IFN-independent STAT protein degradation complex that contains at least STAT1 and STAT2. ..
  42. Morrison J, Aguirre S, Fernandez Sesma A. Innate immunity evasion by Dengue virus. Viruses. 2012;4:397-413 pubmed publisher
    ..In this review, we will evaluate the contribution of innate immunity evasion by DENV to the pathogenesis and host tropism of this virus. ..
  43. R thlisberger A, Wiener D, Schweizer M, Peterhans E, Zurbriggen A, Plattet P. Two domains of the V protein of virulent canine distemper virus selectively inhibit STAT1 and STAT2 nuclear import. J Virol. 2010;84:6328-43 pubmed publisher
    ..Hence, our experiments reveal a novel mechanism of IFN-alpha/beta evasion among the morbilliviruses...
  44. Gupta S, Yan H, Wong L, Ralph S, Krolewski J, Schindler C. The SH2 domains of Stat1 and Stat2 mediate multiple interactions in the transduction of IFN-alpha signals. EMBO J. 1996;15:1075-84 pubmed
    ..In addition, these studies implicate the SH2 domain in another step in the signaling cascade, namely mediation of the interaction between STATs and their activating kinases (i.e. the JAKs). ..
  45. Ramachandran A, Parisien J, Horvath C. STAT2 is a primary target for measles virus V protein-mediated alpha/beta interferon signaling inhibition. J Virol. 2008;82:8330-8 pubmed publisher
    ..These findings clearly define the molecular determinants for measles virus IFN evasion and validate specific targets as candidates for therapeutic intervention. ..
  46. Hengel H, Koszinowski U, Conzelmann K. Viruses know it all: new insights into IFN networks. Trends Immunol. 2005;26:396-401 pubmed
    ..Viral principles might pave the way to develop new therapeutics to modulate immune functions. ..
  47. tenOever B, Ng S, Chua M, McWhirter S, Garcia Sastre A, Maniatis T. Multiple functions of the IKK-related kinase IKKepsilon in interferon-mediated antiviral immunity. Science. 2007;315:1274-8 pubmed
    ..We conclude that IKKepsilon plays a critical role in the IFN-inducible antiviral transcriptional response. ..
  48. Parisien J, Lau J, Rodriguez J, Sullivan B, Moscona A, Parks G, et al. The V protein of human parainfluenza virus 2 antagonizes type I interferon responses by destabilizing signal transducer and activator of transcription 2. Virology. 2001;283:230-9 pubmed
    ..No V-protein-specific effects on STAT2 mRNA levels were observed. The results indicate that the V protein of HPIV2 is sufficient to recognize and target a specific cellular transcription factor for destruction by cellular machinery...
  49. Gupta S, Jiang M, Pernis A. IFN-alpha activates Stat6 and leads to the formation of Stat2:Stat6 complexes in B cells. J Immunol. 1999;163:3834-41 pubmed
    ..Activation of Stat6 as well as of Stat2:Stat6 complexes by IFN-alpha in B cells may allow modulation of target genes in a cell type-specific manner. ..
  50. Mazzon M, Jones M, Davidson A, Chain B, Jacobs M. Dengue virus NS5 inhibits interferon-alpha signaling by blocking signal transducer and activator of transcription 2 phosphorylation. J Infect Dis. 2009;200:1261-70 pubmed publisher
    ..NS5 alone did not, however, induce degradation of STAT2, which occurs when all nonstructural proteins are expressed together. We conclude that DENV NS5 is a potent and specific type I IFN antagonist. ..
  51. Ashour J, Morrison J, Laurent Rolle M, Belicha Villanueva A, Plumlee C, Bernal Rubio D, et al. Mouse STAT2 restricts early dengue virus replication. Cell Host Microbe. 2010;8:410-21 pubmed publisher
    ..These results suggest that overcoming this restriction through transgenic mouse technology may help in the development of a long-sought immune-competent mouse model of dengue virus infection. ..
  52. Kraus T, Lau J, Parisien J, Horvath C. A hybrid IRF9-STAT2 protein recapitulates interferon-stimulated gene expression and antiviral response. J Biol Chem. 2003;278:13033-8 pubmed
    ..The antiviral state generated by regulated IRF9-STAT2 hybrid protein expression is independent of autocrine IFN signaling and inhibits both RNA and DNA viruses. ..
  53. Nishio M, Tsurudome M, Ito M, Garcin D, Kolakofsky D, Ito Y. Identification of paramyxovirus V protein residues essential for STAT protein degradation and promotion of virus replication. J Virol. 2005;79:8591-601 pubmed publisher
    ..Interestingly, many of the residues that are essential for anti-IFN activity, e.g., the Cys of this cluster and Phe207 within this cluster, as well as the Trp of this motif, are also essential for promoting virus growth...