title: Pellino3 targets the IRF7 pathway and facilitates autoregulation of TLR3- and viral-induced expression of type I interferons.
abstract: Toll-like receptors (TLRs) sense pathogen-associated molecules and respond by inducing cytokines and type I interferon. Here we show that genetic ablation of the E3 ubiquitin ligase Pellino3 augmented the expression of type I interferon but not of proinflammatory cytokines in response to TLR3 activation. Pellino3-deficient mice had greater resistance against the pathogenic and lethal effects of encephalomyocarditis virus (EMCV). TLR3 signaling induced Pellino3, which in turn interacted with and ubiquitinated TRAF6. This modification suppressed the ability of TRAF6 to interact with and activate IRF7, resulting in downregulation of type I interferon expression. Our findings highlight a new physiological role for Pellino3 and define a new autoregulatory network for controlling type I interferon expression.
authors.affiliation: Department of Biology, Institute of Immunology, National University of Ireland Maynooth, Maynooth, County Kildare, Ireland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Siednienko
authors.forename: Ruaidhri
authors.initials: R
authors.lastname: Jackson
authors.forename: Mark
authors.initials: M
authors.lastname: Mellett
authors.forename: Nezira
authors.initials: N
authors.lastname: Delagic
authors.forename: Shuo
authors.initials: S
authors.lastname: Yang
authors.forename: Bingwei
authors.initials: B
authors.lastname: Wang
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Tang
authors.forename: John J
authors.initials: JJ
authors.lastname: Callanan
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Mahon
authors.forename: Paul N
authors.initials: PN
authors.lastname: Moynagh
mesh_terms: D000818:Animals; D018188:Cardiovirus Infections / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000821:virology; D004686:Encephalomyocarditis virus / Q000276:immunology; D005786:Gene Expression Regulation; D006706:Homeostasis; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000276:immunology; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D015996:Survival Rate; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000276:immunology*; D025801:Ubiquitin / Q000235:genetics / Q000276:immunology; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D054875:Ubiquitination
chemical_list: D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; C494235:Irf7 protein, mouse; C519703:TLR3 protein, mouse; D048029:TNF Receptor-Associated Factor 6; D051196:Toll-Like Receptor 3; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases