title: [Nucleic acids recognition by innate immunity].
abstract: The innate immune system detects pathogen-derived nucleic acids (DNA and RNA) and induces type I interferon (IFN) and other cytokines, resulting in the host defense against pathogen. We identified interferon-inducible tripartite-motif (TRIM) 56 as a regulator of double-stranded DNA-mediated type I interferon induction. TRIM56 interacted with STING and targeted it for lysine 63-linked ubiquitination. This modification induced STING dimerization, which was a prerequisite for recruitment of the antiviral kinase TBK1 and subsequent induction of IFN-beta. Taken together, these results show that TRIM56 is an interferon-inducible E3 ubiquitin ligase that modulates STING to confer double-stranded DNA-mediated innate immune responses. It is well known that Toll-like receptor 7 (TLR7) and TLR9 sense viral nucleic acids and induce production of type I interferon (IFN) by plasmacytoid dendritic cells (pDCs) to protect the host from virus infection. We showed that the IFN-inducible antiviral protein Viperin promoted TLR7- and TLR9-mediated production of type I IFN by pDCs. Viperin expression was potently induced after TLR7 or TLR9 stimulation and Viperin localized to the cytoplasmic lipid-enriched compartments, lipid bodies, in pDCs. Viperin interacted with the signal mediators IRAK1 and TRAF6 to recruit them to the lipid bodies and facilitated K63-linked ubiquitination of IRAK1 to induce the nuclear translocation of transcription factor IRF7. Thus, besides direct inhibition of viral replication, this finding reveals that Viperin mediates its antiviral function via the regulation of the TLR7 and TLR9-IRAK1 signaling axis in pDCs.
authors.affiliation: Laboratory of Host Defense, WPI Immunology Frontier Research Center (IFReC), Osaka University Department of Host Defense, Research Institute for Microbial Diseases. sakira@biken.osaka-u.ac.jp
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Saitoh
authors.forename: Taro
authors.initials: T
authors.lastname: Kawai
mesh_terms: D000818:Animals; D004269:DNA, Bacterial / Q000276:immunology*; D004279:DNA, Viral / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I / Q000096:biosynthesis; D053592:Interleukin-1 Receptor-Associated Kinases / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011506:Proteins / Q000276:immunology; D012329:RNA, Bacterial / Q000276:immunology*; D012367:RNA, Viral / Q000276:immunology*; D015398:Signal Transduction; D051199:Toll-Like Receptor 7 / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000276:immunology; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000276:immunology*; D054875:Ubiquitination; D000099197:STING Protein; D000090123:Viperin Protein
chemical_list: D004269:DNA, Bacterial; D004279:DNA, Viral; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D053592:Interleukin-1 Receptor-Associated Kinases; D008565:Membrane Proteins; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011506:Proteins; D012329:RNA, Bacterial; D012367:RNA, Viral; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases; C532857:STING1 protein, human; D000099197:STING Protein; C495348:TLR7 protein, human; C444427:RSAD2 protein, human; D000090123:Viperin Protein; C554560:TRIM56 protein, human; C507768:IRAK1 protein, human