title: Lipopolysaccharide-mediated interferon regulatory factor activation involves TBK1-IKKepsilon-dependent Lys(63)-linked polyubiquitination and phosphorylation of TANK/I-TRAF.
abstract: Type I interferon gene induction relies on IKK-related kinase TBK1 and IKKepsilon-mediated phosphorylations of IRF3/7 through the Toll-like receptor-dependent signaling pathways. The scaffold proteins that assemble these kinase complexes are poorly characterized. We show here that TANK/ITRAF is required for the TBK1- and IKKepsilon-mediated IRF3/7 phosphorylations through some Toll-like receptor-dependent pathways and is part of a TRAF3-containing complex. Moreover, TANK is dispensable for the early phase of double-stranded RNA-mediated IRF3 phosphorylation. Interestingly, TANK is heavily phosphorylated by TBK1-IKKepsilon upon lipopolysaccharide stimulation and is also subject to lipopolysaccharide- and TBK1-IKKepsilon-mediated Lys(63)-linked polyubiquitination, a mechanism that does not require TBK1-IKKepsilon kinase activity. Thus, we have identified TANK as a scaffold protein that assembles some but not all IRF3/7-phosphorylating TBK1-IKKepsilon complexes and demonstrated that these kinases possess two functions, namely the phosphorylation of both IRF3/7 and TANK as well as the recruitment of an E3 ligase for Lys(63)-linked polyubiquitination of their scaffold protein, TANK.
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics, Medical Chemistry, and Virology/Immunology units, University of Liege, Sart-Tilman, 4000 Liège, Belgium.
authors.forename: Jean-Stéphane
authors.initials: JS
authors.lastname: Gatot
authors.forename: Romain
authors.initials: R
authors.lastname: Gioia
authors.forename: Tieu-Lan
authors.initials: TL
authors.lastname: Chau
authors.forename: Félicia
authors.initials: F
authors.lastname: Patrascu
authors.forename: Michael
authors.initials: M
authors.lastname: Warnier
authors.forename: Pierre
authors.initials: P
authors.lastname: Close
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Chapelle
authors.forename: Eric
authors.initials: E
authors.lastname: Muraille
authors.forename: Keith
authors.initials: K
authors.lastname: Brown
authors.forename: Ulrich
authors.initials: U
authors.lastname: Siebenlist
authors.forename: Jacques
authors.initials: J
authors.lastname: Piette
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Dejardin
authors.forename: Alain
authors.initials: A
authors.lastname: Chariot
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation / Q000276:immunology; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000276:immunology* / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000276:immunology / Q000378:metabolism; D007668:Kidney / Q000166:cytology; D008070:Lipopolysaccharides / Q000276:immunology* / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008239:Lysine / Q000737:chemistry / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000276:immunology* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014162:Transfection; D020798:Two-Hybrid System Techniques; D054875:Ubiquitination