The TRAF-associated protein TANK facilitates cross-talk within the I kappa B kinase family during Toll-like receptor signaling

Kristopher Clark, Osamu Takeuchi, Shizuo Akira, Philip Cohen

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    Abstract

    Toll-like receptor (TLR) ligands that signal via TIR-domain-containing adapter-inducing IFN beta (TRIF) activate the I kappa B kinase (IKK)-related kinases, TRAF associated NF kappa B activator (TANK)-binding kinase-1 (TBK1) and IKK epsilon, which then phosphorylate IRF3 and induce the production of IFN beta. Here we show that TBK1 and IKK epsilon are also activated by TLR ligands that signal via MyD88. Notably, the activation of IKK epsilon is rapid, transient, and it precedes a more prolonged activation of TBK1. The MyD88- and TRIF-dependent signaling pathways activate the IKK-related kinases by two signaling pathways. One is mediated by the canonical IKKs, whereas the other culminates in the autoactivation of the IKK-related kinases. Once activated, TBK1/IKK epsilon then phosphorylate and inhibit the canonical IKKs. The negative regulation of the canonical IKKs by the IKK-related kinases occurs in both the TRIF- and MyD88-dependent TLR pathways, whereas IRF3 phosphorylation is restricted to the TRIF-dependent signaling pathway. We have discovered that the activation of IKK epsilon is abolished, the activation of TBK1 is reduced, and the interaction between the IKK-related kinases and the canonical IKKs is suppressed in TANK(-/-) macrophages, preventing the IKK-related kinases from negatively regulating the canonical IKKs. In contrast, IRF3 phosphorylation and IFN beta production was normal in TANK(-/-) macrophages. Our results demonstrate a key role for TANK in enabling the canonical IKKs and the IKK-related kinases to regulate each other, which is required to limit the strength of TLR signaling and ultimately, prevent autoimmunity.

    Original languageEnglish
    Pages (from-to)17093-17098
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume108
    Issue number41
    DOIs
    Publication statusPublished - 11 Oct 2011

    Keywords

    • IKK-EPSILON
    • POLYUBIQUITIN BINDING
    • ANTIVIRAL RESPONSE
    • NF-KAPPA-B1 P105
    • VIRAL-INFECTION
    • INNATE IMMUNITY
    • ACTIVATION
    • TBK1
    • LIPOPOLYSACCHARIDE
    • PATHWAY

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