title: E3 ligase WWP2 negatively regulates TLR3-mediated innate immune response by targeting TRIF for ubiquitination and degradation.
abstract: Recognition of viral double-stranded RNA by Toll-like receptor 3 (TLR3) triggers activation of the transcription factors NF-κB and interferon regulated factor 3, leading to induction of type I interferons and proinflammatory cytokines. TIR-domain-containing adapter-inducing interferon-β (TRIF) is an adapter protein required for TLR3-mediated signaling. Here we identified the E3 ubiquitin ligase WW domain-containing protein 2 (WWP2) as a TRIF-associated protein by biochemical purification. WWP2 mediated K48-linked ubiquitination and degradation of TRIF upon TLR3 activation. Overexpression of WWP2 inhibited TLR3-mediated NF-κB and interferon regulated factor 3 activation, whereas knockdown of WWP2 had opposite effects. We generated Wwp2-deficient mice to further investigate the roles of Wwp2 in innate immune responses. Consistently, production of IFN-β, CCL5, TNFα, and IL-6 in response to the TLR3 ligand poly(I:C) was elevated in Wwp2(-/-) macrophages and Wwp2-deficient mice exhibited increased susceptibility to poly(I:C)-induced death than the control littermates. Our findings suggest that WWP2 negatively regulates TLR3-mediated innate immune and inflammatory responses by targeting TRIF for ubiquitination and degradation.
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.forename: Bing
authors.initials: B
authors.lastname: Liao
authors.forename: Suyun
authors.initials: S
authors.lastname: Wang
authors.forename: Bingru
authors.initials: B
authors.lastname: Yan
authors.forename: Ying
authors.initials: Y
authors.lastname: Jin
authors.forename: Hong-Bing
authors.initials: HB
authors.lastname: Shu
authors.forename: Yan-Yi
authors.initials: YY
authors.lastname: Wang
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology*; D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D007369:Interferon Inducers / Q000494:pharmacology; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D011070:Poly I-C / Q000494:pharmacology; D059748:Proteolysis; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology*; D054875:Ubiquitination / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D007369:Interferon Inducers; D050838:Interferon Regulatory Factor-3; D016328:NF-kappa B; D011070:Poly I-C; D051196:Toll-Like Receptor 3; D044767:Ubiquitin-Protein Ligases; C494233:Irf3 protein, mouse; C476286:Ticam1 protein, mouse; C519703:TLR3 protein, mouse; C487995:Wwp2 protein, mouse