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, 282 (43), 31131-46

Lipopolysaccharide-mediated Interferon Regulatory Factor Activation Involves TBK1-IKKepsilon-dependent Lys(63)-linked Polyubiquitination and Phosphorylation of TANK/I-TRAF

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Lipopolysaccharide-mediated Interferon Regulatory Factor Activation Involves TBK1-IKKepsilon-dependent Lys(63)-linked Polyubiquitination and Phosphorylation of TANK/I-TRAF

Jean-Stéphane Gatot et al. J Biol Chem.

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.

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