Virus Infection Triggers SUMOylation of IRF3 and IRF7, Leading to the Negative Regulation of Type I Interferon Gene Expression

Abstract

Viral infection activates Toll-like receptor and RIG-I (retinoic acid-inducible gene I) signaling pathways, leading to phosphorylation of IRF3 (interferon regulatory factor 3) and IRF7 and stimulation of type I interferon (IFN) transcription, a process important for innate immunity. We show that upon vesicular stomatitis virus infection, IRF3 and IRF7 are modified not only by phosphorylation but by the small ubiquitin-related modifiers SUMO1, SUMO2, and SUMO3. SUMOylation of IRF3 and IRF7 was dependent on the activation of Toll-like receptor and RIG-I pathways but not on the IFN-stimulated pathway. However, SUMOylation of IRF3 and IRF7 was not dependent on their phosphorylation, and vice versa. We identified Lys152 of IRF3 and Lys406 of IRF7 to be their sole small ubiquitin-related modifier (SUMO) conjugation site. IRF3 and IRF7 mutants defective in SUMOylation led to higher levels of IFN mRNA induction after viral infection, relative to the wild type IRFs, indicating a negative role for SUMOylation in IFN transcription. Together, SUMO modification is an integral part of IRF3 and IRF7 activity that contributes to postactivation attenuation of IFN production. Viral infection activates Toll-like receptor and RIG-I (retinoic acid-inducible gene I) signaling pathways, leading to phosphorylation of IRF3 (interferon regulatory factor 3) and IRF7 and stimulation of type I interferon (IFN) transcription, a process important for innate immunity. We show that upon vesicular stomatitis virus infection, IRF3 and IRF7 are modified not only by phosphorylation but by the small ubiquitin-related modifiers SUMO1, SUMO2, and SUMO3. SUMOylation of IRF3 and IRF7 was dependent on the activation of Toll-like receptor and RIG-I pathways but not on the IFN-stimulated pathway. However, SUMOylation of IRF3 and IRF7 was not dependent on their phosphorylation, and vice versa. We identified Lys152 of IRF3 and Lys406 of IRF7 to be their sole small ubiquitin-related modifier (SUMO) conjugation site. IRF3 and IRF7 mutants defective in SUMOylation led to higher levels of IFN mRNA induction after viral infection, relative to the wild type IRFs, indicating a negative role for SUMOylation in IFN transcription. Together, SUMO modification is an integral part of IRF3 and IRF7 activity that contributes to postactivation attenuation of IFN production. Invading pathogens are recognized by Toll-like receptors (TLRs) 3The abbreviations used are: TLRToll-like receptorIRFinterferon regulatory factorIFNinterferonUblubiquitin-like proteinSUMOsmall ubiquitin-related modifierVSVvesicular stomatitis virusEMCVencephalomyocarditis virusMOImultiplicity of infectionshRNAshort hairpin RNAWTwild typeJAKJanus kinaseSTATsignal transducers and activators of transcriptionHDAChistone deacetylase. and/or RNA helicases (i.e. RIG-I/MDA-5 (retinoic acid-inducible gene I/melanoma differentiation-associated gene 5)) (1Akira S. Uematsu S. Takeuchi O. Cell. 2006; 124: 783-801Abstract Full Text Full Text PDF PubMed Scopus (9171) Google Scholar, 2Andrejeva J. Childs K.S. Young D.F. Carlos T.S. Stock N. Good-bourn S. Randall R.E. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 17264-17269Crossref PubMed Scopus (834) Google Scholar, 3Kawai T. Akira S. Nat. Immunol. 2006; 7: 131-137Crossref PubMed Scopus (1480) Google Scholar, 4Takeda K. Akira S. Int. Immunol. 2005; 17: 1-14Crossref PubMed Scopus (2778) Google Scholar, 5Yoneyama M. Kikuchi M. Natsukawa T. Shinobu N. Imaizumi T. Miyagishi M. Taira K. Akira S. Fujita T. Nat. Immunol. 2004; 5: 730-737Crossref PubMed Scopus (3188) Google Scholar). Binding of pathogen components to these molecules activates downstream signaling pathways, which results in the production of various proinflammatory cytokines, important for the establishment of innate and adaptive immunity (3Kawai T. Akira S. Nat. Immunol. 2006; 7: 131-137Crossref PubMed Scopus (1480) Google Scholar). Among them, type I interferons (IFNs) play a major role in conferring antiviral and antimicrobial activities (6Durbin J.E. Fernandez-Sesma A. Lee C.K. Rao T.D. Fery A.B. Moran T.M. Vukmanovic S. Garcia-Sastre A. Levy D.E. J. Immunol. 2000; 164: 4220-4228Crossref PubMed Scopus (236) Google Scholar, 7Hengel H. Koszinowski U.H. Conzelmann K.K. Trends Immunol. 2005; 26: 396-401Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 8Levy D.E. Garcia-Sastre A. Cytokine Growth Factor Rev. 2001; 12: 143-156Crossref PubMed Scopus (356) Google Scholar). Production of type I IFN depends on activation of IRF3 (interferon regulatory factor 3) and IRF7 (3Kawai T. Akira S. Nat. Immunol. 2006; 7: 131-137Crossref PubMed Scopus (1480) Google Scholar, 9Honda K. Taniguchi T. Nat. Rev. Immunol. 2006; 6: 644-658Crossref PubMed Scopus (1324) Google Scholar, 10Fitzgerald K.A. McWhirter S.M. Faia K.L. Rowe D.C. Katz E. Golenbock D.T. Cole A.J. Liao S.M. Maniatis T. Nat. Immunol. 2003; 4: 491-496Crossref PubMed Scopus (2165) Google Scholar, 11Honda K. Takaoka A. Taniguchi T. Immunity. 2006; 25: 349-360Abstract Full Text Full Text PDF PubMed Scopus (997) Google Scholar). IRF3 and IRF7 are phosphorylated by TBK-1 (TANK-binding kinase 1) and IKKϵ (IκB kinase ϵ), dimerized, translocated into the nucleus, and finally stimulate IFN gene transcription (3Kawai T. Akira S. Nat. Immunol. 2006; 7: 131-137Crossref PubMed Scopus (1480) Google Scholar, 9Honda K. Taniguchi T. Nat. Rev. Immunol. 2006; 6: 644-658Crossref PubMed Scopus (1324) Google Scholar, 10Fitzgerald K.A. McWhirter S.M. Faia K.L. Rowe D.C. Katz E. Golenbock D.T. Cole A.J. Liao S.M. Maniatis T. Nat. Immunol. 2003; 4: 491-496Crossref PubMed Scopus (2165) Google Scholar, 11Honda K. Takaoka A. Taniguchi T. Immunity. 2006; 25: 349-360Abstract Full Text Full Text PDF PubMed Scopus (997) Google Scholar). Toll-like receptor interferon regulatory factor interferon ubiquitin-like protein small ubiquitin-related modifier vesicular stomatitis virus encephalomyocarditis virus multiplicity of infection short hairpin RNA wild type Janus kinase signal transducers and activators of transcription histone deacetylase. Ubiquitin-like proteins (Ubls), including the small ubiquitin-related modifiers (SUMO) and ISG15 (interferon stimulated gene 15), among others, modify many proteins to regulate various biological processes (12Gill G. Gene Dev. 2004; 18: 2046-2059Crossref PubMed Scopus (633) Google Scholar, 13Gill G. Curr. Opin. Genet. Dev. 2005; 15: 536-541Crossref PubMed Scopus (426) Google Scholar, 14Hay R.T. Mol. Cell. 2005; 18: 1-12Abstract Full Text Full Text PDF PubMed Scopus (1360) Google Scholar, 15Schwartz D.C. Hochstrasser M. Trends Biochem. Sci. 2003; 28: 321-328Abstract Full Text Full Text PDF PubMed Scopus (321) Google Scholar). Ubls are conjugated to target proteins by an enzymatic cascade involving an activating enzyme (E1), a conjugating enzyme (E2), and a ligase (E3) (15Schwartz D.C. Hochstrasser M. Trends Biochem. Sci. 2003; 28: 321-328Abstract Full Text Full Text PDF PubMed Scopus (321) Google Scholar, 16Hodges M. Tissot C. Freemont P.S. Curr. Biol. 1998; 8: R749-R752Abstract Full Text Full Text PDF PubMed Google Scholar, 17Huang D.T. Walden H. Duda D. Schulman B.A. Oncogene. 2004; 23: 1958-1971Crossref PubMed Scopus (66) Google Scholar). Ubl modification of signaling molecules and transcription factors has a large impact on gene expression (13Gill G. Curr. Opin. Genet. Dev. 2005; 15: 536-541Crossref PubMed Scopus (426) Google Scholar, 14Hay R.T. Mol. Cell. 2005; 18: 1-12Abstract Full Text Full Text PDF PubMed Scopus (1360) Google Scholar). Type I IFN induction involves ubiquitin and Ubl modifications of multiple signaling molecules. For example, RIG-I is modified by ubiquitin by at least two independent E3 ligases, TRIM25 and RNF125, to positively and negatively regulate type I IFN production, respectively (18Arimoto K. Takahashi H. Hishiki T. Konishi H. Fujita T. Shimotohno K. Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 7500-7505Crossref PubMed Scopus (373) Google Scholar-20). RIG-I is also modified by ISG15 (19Arimoto K. Konishi H. Shimotohno K. Mol. Immunol. 2008; 45: 1078-1084Crossref PubMed Scopus (49) Google Scholar, 21Kim M.J. Hwang S.Y. Imaizumi T. Yoo J.Y. J. Virol. 2008; 82: 1474-1483Crossref PubMed Scopus (194) Google Scholar, 22Zhao C. Denison C. Huibregtse J.M. Gygi S. Kreg R.M. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 10200-10205Crossref PubMed Scopus (374) Google Scholar). Furthermore, IRF7 is ubiquitinated by TRAF6, an event believed to be important for type I IFN transcription (23Kawai T. Sato S. Ishii K.J. Coban C. Hemmi H. Yamamoto M. Terai K. Matsuda M. Inoue J.I. Uematsu S. Takeuchi O. Akira S. Nat. Immunol. 2004; 5: 1061-1068Crossref PubMed Scopus (854) Google Scholar). IRF7 is reported to interact with the TNF receptor-associated adaptor protein RIP in the presence of an EBV oncoprotein, which enhances IRF7 ubiquitination and activation (24Huye L.E. Ning S. Kelliher M. Pagano J.S. Mol. Cell. Biol. 2007; 27: 2910-2918Crossref PubMed Scopus (67) Google Scholar). The SUMO proteins, ∼12 kDa in size, covalently attach to many proteins (13Gill G. Curr. Opin. Genet. Dev. 2005; 15: 536-541Crossref PubMed Scopus (426) Google Scholar, 14Hay R.T. Mol. Cell. 2005; 18: 1-12Abstract Full Text Full Text PDF PubMed Scopus (1360) Google Scholar, 25Geiss-Friedlander R. Melchior F. Nat. Rev. Mol. Cell. Biol. 2007; 8: 947-956Crossref PubMed Scopus (1416) Google Scholar). are at least SUMO and and a are to in the in only but are with which only R.T. Mol. Cell. 2005; 18: 1-12Abstract Full Text Full Text PDF PubMed Scopus (1360) Google Scholar). and to modify and including a of transcription factors (13Gill G. Curr. Opin. Genet. Dev. 2005; 15: 536-541Crossref PubMed Scopus (426) Google Scholar, 14Hay R.T. Mol. Cell. 2005; 18: 1-12Abstract Full Text Full Text PDF PubMed Scopus (1360) Google Scholar). proteins the is a is and is the SUMO C. R.T. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). The SUMO conjugating the and SUMO to the in the (12Gill G. Gene Dev. 2004; 18: 2046-2059Crossref PubMed Scopus (633) Google Scholar). SUMOylation of transcription factors is with are (13Gill G. Curr. Opin. Genet. Dev. 2005; 15: 536-541Crossref PubMed Scopus (426) Google Scholar, 14Hay R.T. Mol. Cell. 2005; 18: 1-12Abstract Full Text Full Text PDF PubMed Scopus (1360) Google Scholar). factors of the regulate the type I IFN induction of to IFN K. Taniguchi T. Nat. Rev. Immunol. 2006; 6: 644-658Crossref PubMed Scopus (1324) Google Scholar, 11Honda K. Takaoka A. Taniguchi T. Immunity. 2006; 25: 349-360Abstract Full Text Full Text PDF PubMed Scopus (997) Google Scholar, K. T. J. Biol. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). Among is to be covalently conjugated to SUMO1, and SUMOylation to be to K. H. PubMed Scopus Google Scholar). by of the are also show IRF3 and IRF7 are covalently conjugated to SUMO1, SUMO2, and and the SUMOylation of IRF3 and IRF7 was virus SUMOylation of IRF3 and IRF7 was a of and RIG-I activation but not of IFN We also that of SUMOylation IRF3 and IRF7 the of SUMOylation to and mRNA expression viral the that IRF3 and IRF7 SUMOylation postactivation attenuation of IFN gene transcription. and protein for the and and for the and and and and IRF3 was and was was and and and G. of in modified in modified For virus was the and with vesicular stomatitis virus encephalomyocarditis virus at an of for was to the and the was to for the of of SUMO2, and RNA by and into with a at the a at the mutants for IRF3 and into the and the a was a H. of was by of the with For an an was into to the a a with a was and in of SUMO conjugation of IRF3 and with a of of and stimulated with for and in and and with with at with and on and to For IRF3 and by at an of for the of with of IRF3 and protein at with and by the with with a of expression after in on with to the For with in at for with and on with with of after with at an of for the RNA with the was with the The of and by and to the for by the IRF3 and IRF7 by SUMO1, and IRF7 has a to be conjugated to SUMO IRF7 was into with with and for by of kDa that with for was in with and in was not in with the of to be ∼12 kDa and that of IRF7 to be kDa was to be a was with IRF7 a kDa with with a with a SUMO and SUMOylation of IRF7 and IRF3 by not results that IRF3 and IRF7 be modified by SUMO1, and of SUMO in IRF3 and on the two SUMOylation in IRF7 that the and in IRF3 these are SUMO conjugation a was into of these in IRF3 and and the mutants for SUMO in the IRF7 to wild type IRF7 and the IRF7 was at levels with IRF7 indicating that the of SUMOylation in was not to a protein For mutants conjugated to was for IRF3 in which the was in the to that of IRF7 was results IRF7 and IRF3 mutants with not results that Lys406 of IRF7 and Lys152 of IRF3 a conjugation for SUMO1, and SUMOylation of IRF3 and that IRF3 and IRF7 SUMO1, and was of to that SUMOylation of IRF3 and that IRF3 and IRF7 are upon virus infection, their SUMOylation is stimulated by virus and and with and IRF7 SUMOylation was by and SUMO conjugation was viral However, IRF7 a in and conjugation at and after virus infection led to SUMOylation of IRF3 with and and the levels of SUMOylation the at after viral infection for IRF3 and SUMO conjugation was at for SUMOylation after viral infection was not to in the expression levels for for after viral infection We important to IRF3 and IRF7 are in a with and IRF3 for with in of IRF3 was infection, and IRF3 was at and after infection the kDa in the The of SUMO conjugation was at with the in results that infection SUMOylation of the of the IRF3 the of for a sole enzyme for SUMO conjugation (12Gill G. Gene Dev. 2004; 18: 2046-2059Crossref PubMed Scopus (633) Google Scholar, 13Gill G. Curr. Opin. Genet. Dev. 2005; 15: 536-541Crossref PubMed Scopus (426) Google Scholar, 14Hay R.T. Mol. Cell. 2005; 18: 1-12Abstract Full Text Full Text PDF PubMed Scopus (1360) Google Scholar). of the expression IRF3 expression in IRF3 SUMOylation was in these indicating that SUMOylation was dependent on and the SUMOylation be that was not to SUMOylation of IRF7 modifications to their expression SUMOylation of IRF3 and IRF7 Type I IFN Gene SUMOylation to the that SUMO modification activity of IRF3 and in SUMOylation in IRF3 and IRF7 type I IFN with IRF7 the IRF7 stimulated with for and mRNA levels by and of IRF7 IFN upon of IRF7 led to a in the expression of mRNA and mRNA infection relative to IRF7 of IRF7 and the was of viral infection that by of was not and that the IRF7 in IFN the in IFN mRNA expression by the Lys406 an with IRF3 and the are in and D. with the for the higher levels of mRNA and mRNA with IRF3 upon the higher induction upon infection with the type I IFN mRNA expression by the was at after infection and was not at which in with IRF3 and IRF7 SUMOylation after virus infection with in results that SUMOylation of IRF3 and IRF7 negatively regulate type I IFN and RIG-I/MDA-5 SUMOylation of IRF3 and that virus SUMOylation of IRF3 and IRF7 to of type I IFN transcription. We signaling pathways that SUMOylation of IRF3 and is a signaling in the (3Kawai T. Akira S. Nat. Immunol. 2006; 7: 131-137Crossref PubMed Scopus (1480) Google Scholar, Rowe D. G. Int. J. Biochem. Biol. 2007; PubMed Scopus Google and IRF3 and IRF7 T. Sato S. Coban C. H. H. Ishii K.J. Takeuchi O. Akira S. Nat. Immunol. 2005; 6: PubMed Scopus Google Scholar, E. J. K. D. M. R. J. 2005; PubMed Scopus Google Scholar, C.K. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, K.J. Mol. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). of led to SUMOylation of IRF3 in a SUMOylation of IRF7 was also by of is an adaptor the signaling and expression results in activation of IRF3 and IRF7 H. M. K. T. T. Nat. Immunol. 2003; 4: PubMed Scopus Google Scholar, M. Sato S. K. K. Takeuchi O. K. Akira S. J. Immunol. PubMed Scopus Google Scholar). to of IRF3 results that IRF3 and IRF7 are a of and RIG-I/MDA-5 SUMOylation of and IRF7 are phosphorylated in to and RIG-I/MDA-5 their activation (3Kawai T. Akira S. Nat. Immunol. 2006; 7: 131-137Crossref PubMed Scopus (1480) Google Scholar, 11Honda K. Takaoka A. Taniguchi T. Immunity. 2006; 25: 349-360Abstract Full Text Full Text PDF PubMed Scopus (997) Google Scholar). We to phosphorylation and SUMOylation of IRF3 and IRF7 and in a dependent IRF3 and IRF3 the be phosphorylated upon phosphorylated the was in which phosphorylated proteins E. E. K. T. Mol. Cell. 2005; 5: Full Text Full Text PDF PubMed Scopus Google Scholar). in with IRF3 and IRF3 multiple IRF3 in to the IRF3 in a The by the IRF3 and IRF3 in the to The of the IRF3 after was to phosphorylation, these was in IRF3 and IRF3 which was after indicating a of the not IRF3 and IRF3 to a of results show that activation to IRF3 phosphorylation in IRF3 and IRF3 indicating that phosphorylation of IRF3 not IRF3 and IRF7 SUMOylation on to SUMOylation of IRF3 and IRF7 is dependent on mutants defective in phosphorylation at and in IRF7 and at and in IRF3 by to and are phosphorylated after and their the activation A. Levy D.E. J. Biol. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, R. C. J. Mol. Cell. Biol. 1998; 18: PubMed Scopus Google Scholar, M. M. T. Takahashi K. F. Fujita T. J. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, M. N. D. R. J. J. Biol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). We also of IRF3 and IRF7 by and with and in A. Levy D.E. J. Biol. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, R. C. J. Mol. Cell. Biol. 1998; 18: PubMed Scopus Google Scholar, M. M. T. Takahashi K. F. Fujita T. J. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, M. N. D. R. J. J. Biol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). not in and in the the of these mutants to be phosphorylated and However, IRF3 and in the presence of SUMO1, in a SUMOylation was not IRF3 and the of and to the was also after infection in a to IRF3 and the for the of IRF3 and by for was the IRF7 in the presence of SUMO1, and mutants not results that SUMOylation of IRF3 and IRF7 not on their with SUMOylation of IRF3 and the of IRF3 and IRF7 and in in a the wild type proteins and that SUMOylation of IRF3 and IRF7 of their The Type I to IRF3 and IRF7 of IRF3 and IRF7 downstream of and RIG-I/MDA-5 pathways that activation of these pathways to type I IFN production (3Kawai T. Akira S. Nat. Immunol. 2006; 7: 131-137Crossref PubMed Scopus (1480) Google Scholar, 11Honda K. Takaoka A. Taniguchi T. Immunity. 2006; 25: 349-360Abstract Full Text Full Text PDF PubMed Scopus (997) Google was that type I IFN signaling SUMOylation of IRF3 and a stimulate expression of many the activation of J.E. PubMed Scopus Google an factor be for SUMOylation of IRF3 and these SUMOylation of IRF3 and and with and and SUMOylation of IRF3 IRF7 was at after IRF3 and IRF7 in the presence of SUMO1, to not SUMOylation of IRF3 and of levels of IFN-stimulated and that the was in these and the that induction of and activation of the signaling are not in the SUMOylation of IRF3 and defective in activation S. J.E. Mol. Cell. Biol. 15: PubMed Google Scholar, M. C. J. C. T. J.E. J. 12: PubMed Scopus Google Scholar). the the and the with IRF3 and and for SUMOylation after IRF3 was in in a at and virus infection of and only in not in that signaling was only in the and not in IRF3 was in and not IRF7 was in with infection results that SUMOylation of IRF3 IRF7 a of activation of and RIG-I/MDA-5 pathways and not on the pathway. We that IRF3 and IRF7 are in to virus infection, a at Lys152 and We identified the signaling pathways that SUMOylation of IRF3 and IRF7 was an event downstream of and RIG-I pathways are by a of pathogen RIG-I is by RNA and RNA with (3Kawai T. Akira S. Nat. Immunol. 2006; 7: 131-137Crossref PubMed Scopus (1480) Google Scholar, S. K. A. K. A. K. Fujita T. Conzelmann K.K. A. Mol. Cell. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). IFN was not in the SUMOylation of IRF3 and indicating that SUMOylation is to the pathogen to the SUMOylation of IRF3 and IRF7 is to be a part of innate that SUMOylation type I IFN induction for IRF3 and IRF7 to the that SUMOylation a role in the of IFN transcription after indicating that SUMOylation of IRF3 and IRF7 was after viral also of expression is for the to and after are multiple that attenuation of For example, signaling by pathways is negatively by the proteins of the of that are for of induction Immunity. 2008; 28: Full Text Full Text PDF PubMed Scopus Google Scholar). The of SUMO E3 also signaling by the activity of factors to the and S. K.A. N. C. H. K. Nat. Immunol. 2004; 5: PubMed Scopus Google Scholar, R. K.A. C. N. G. H. K. Mol. Cell. Biol. 2005; 25: PubMed Scopus Google Scholar, H. S. R. S. D. K. Cell. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). of IRF3 and RIG-I also a role in of innate ubiquitination of RIG-I has an role T. C. Takeuchi O. Akira S. Inoue S. 2007; PubMed Scopus Google Scholar, 21Kim M.J. Hwang S.Y. Imaizumi T. Yoo J.Y. J. Virol. 2008; 82: 1474-1483Crossref PubMed Scopus (194) Google Scholar, T. A. A. Yamamoto M. G. Fujita T. Akira S. Yamamoto N. S. Nat. Immunol. 2006; 7: PubMed Scopus Google Scholar). IFN-stimulated of RIG-I activation of downstream target (18Arimoto K. Takahashi H. Hishiki T. Konishi H. Fujita T. Shimotohno K. Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 7500-7505Crossref PubMed Scopus (373) Google Scholar, K. Konishi H. Shimotohno K. Mol. Immunol. 2008; 45: 1078-1084Crossref PubMed Scopus (49) Google Scholar). The multiplicity of negative the presence of that of SUMOylation of IRF3 and IRF7 to the by a that at the of IFN transcription (13Gill G. Curr. Opin. Genet. Dev. 2005; 15: 536-541Crossref PubMed Scopus (426) Google Scholar, 14Hay R.T. Mol. Cell. 2005; 18: 1-12Abstract Full Text Full Text PDF PubMed Scopus (1360) Google Scholar). is that SUMOylation of IRF3 and IRF7 a of activation of a SUMO E3 ligase SUMOylation be a of of a activities of SUMO not has reported that is phosphorylated by and the activation of H. S. R. S. D. K. Cell. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). phosphorylation is to is for the E3 ligase that SUMOylation of IRF3 and IRF7 after virus stimulation has not Among the SUMO E3 ligases, including the proteins, and proteins are to play a role in innate immunity S. K.A. N. C. H. K. Nat. Immunol. 2004; 5: PubMed Scopus Google Scholar, R. K.A. C. N. G. H. K. Mol. Cell. Biol. 2005; 25: PubMed Scopus Google Scholar, F. F. A. Trends Biochem. Sci. 2003; 28: Full Text Full Text PDF PubMed Scopus Google Scholar, C. M. A. D. E. C. R. J. Immunol. 2004; PubMed Scopus Google Scholar, S. K.A. H. K. Proc. Natl. Acad. Sci. U. S. A. 2007; 104: PubMed Scopus Google Scholar). pathways and transcription. of the is reported to be by K. H. PubMed Scopus Google Scholar). a ligase the be a for the SUMOylation of IRF3 and IRF7 after viral of IFN transcription not only IRF3 and IRF7 but transcription For in to and in transcription D. Maniatis T. Cell. Full Text PDF PubMed Scopus Google Scholar). components of the transcription are of modification by and SUMOylation is with transcription G. R. E. R. M. D. S. M. Mol. Cell. Biol. 2005; 25: PubMed Scopus Google Scholar, S. M. F. J.S. A. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). Furthermore, that to is also J.M. R.T. Mol. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). activation by ubiquitination and of be of to virus stimulation SUMOylation of and with that of IRF3 and that SUMOylation of IRF3 and IRF7 is an event independent of their IRF3 and IRF7 phosphorylated of their to be results the that SUMO modification of IRF3 and IRF7 is not to the IRF3 IRF7 but in molecules The of IRF3 and IRF7 for SUMOylation that modification of IRF3 and IRF7 which in after is of that phosphorylation is important for SUMOylation of proteins, and J. M. A. Proc. Natl. Acad. Sci. U. S. A. 2006; PubMed Scopus Google the phosphorylation and SUMOylation are and are these modifications with reported for and G. R. E. R. M. D. S. M. Mol. Cell. Biol. 2005; 25: PubMed Scopus Google Scholar, J.Y. T. Shimotohno K. 2004; PubMed Scopus Google Scholar). has that ubiquitin and SUMO modifications and in are in a J.M. R.T. Mol. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). has that IRF7 is ubiquitinated in to and modification is believed to be important for IFN transcription (23Kawai T. Sato S. Ishii K.J. Coban C. Hemmi H. Yamamoto M. Terai K. Matsuda M. Inoue J.I. Uematsu S. Takeuchi O. Akira S. Nat. Immunol. 2004; 5: 1061-1068Crossref PubMed Scopus (854) Google Scholar). is not SUMOylation of IRF7 ubiquitination vice versa. the is reported that IRF3 with and is by a by ubiquitination T. A. A. Yamamoto M. G. Fujita T. Akira S. Yamamoto N. S. Nat. Immunol. 2006; 7: PubMed Scopus Google Scholar). on that IRF3 is of phosphorylation, IRF3 not to be to that SUMOylation mutants expression of and virus infection is with a of that SUMOylation of transcription factors results in transcription (13Gill G. Curr. Opin. Genet. Dev. 2005; 15: 536-541Crossref PubMed Scopus (426) Google Scholar, 14Hay R.T. Mol. Cell. 2005; 18: 1-12Abstract Full Text Full Text PDF PubMed Scopus (1360) Google Scholar, A. J. M. 2003; 4: PubMed Scopus Google Scholar). with the of histone has that to target G. S. A. T.M. C.K. 2005; PubMed Scopus Google Scholar). to and of leading to activity Mol. Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). the is the and to with D. D. A. E. R.T. Mol. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). a role of in is modified by SUMO G. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). with these SUMO modification of IRF3 and IRF7 to IFN in a leading to in to the is to histone upon viral stimulation T. S. J. Maniatis T. D. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google is that IRF3 and IRF7 an to a by is also with in of transcription reported for S. G. Mol. Cell. Full Text Full Text PDF PubMed Scopus (321) Google and G. J. R. Dev. 2003; 17: PubMed Scopus Google Scholar). factor and not be be of to IRF3 and IRF7 IRF3 and IRF7 are modified by SUMO viral infection, and modification the and of IFN transcription, to of IFN production We and for the of and and R. for the of and with