Identification of the protein kinases that activate the E3 ubiquitin ligase Pellino 1 in the innate immune system

Eddy T. H. Goh, J. Simon C. Arthur, Peter C. F. Cheung, Shizuo Akira, Rachel Toth, Philip Cohen

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    Abstract

    The E3 ubiquitin ligase Pellino 1 can be interconverted between inactive and active forms by a reversible phosphorylation mechanism. In vitro, phosphorylation and activation can be catalysed by either the IRAKs [IL (interleukin)-1-receptor-associated kinases] IRAK1 and IRAK4, or the IKK {I kappa B [inhibitor of NF-kappa B (nuclear factor kappa B)] kinase}-related kinases [IKK epsilon and TBK1 (TANK {TRAF [TNF (tumour-necrosis-factor)-receptor-associated factor]-associated NF-kappa B activator}-binding kinase 1)]. In the present study we establish that IRAK I is the major protein kinase that mediates the IL-1-stimulated activation of Pellino 1 in MEFs (mouse embryonic fibroblasts) or HEK (human embryonic kidney)-293 cells, whereas the IKK-related kinases activate Pellino 1 in TNF alpha-stimulated MEFs. The IKK-related kinases are also the major protein kinases that activate Pellino 1 in response to TLR (Toll-like receptor) ligands that signal via the adaptors MyD88 (myeloid differentiation primary response gene 88) and/or TRIF [TIR (Toll/IL-1 receptor) domain-containing adaptor protein inducing interferon beta]. The present studies demonstrate that, surprisingly, the ligands that signal via MyD88 do not always employ the same protein kinase to activate Pellino 1. Our results also establish that neither the catalytic activity of IRAK1 nor the activation of Pellino 1 is required for the initial transient activation of NF-kappa B and MAPKs (mitogen-activated protein kinases) that is triggered by IL-1 or TNF alpha in MEFs, or by TLR ligands in macrophages. The activation of Pellino 1 provides the first direct readout for IRAK1 catalytic activity in cells.

    Original languageEnglish
    Pages (from-to)339-346
    Number of pages8
    JournalBiochemical Journal
    Volume441
    DOIs
    Publication statusPublished - 1 Jan 2012

    Keywords

    • interleukin-1-receptor-associated kinase (IRAK)
    • inhibitor of nuclear factor kappa B kinase (IKK)
    • TANK [TRAF (tumour-necrosis-factor-receptor-associated factor)-associated nuclear factor kappa B activator]-binding kinase 1 (TBK1)
    • tumour necrosis factor alpha (TNF alpha)
    • Toll-like receptor (TLR)
    • FHA DOMAIN
    • IRAK1
    • POLYUBIQUITINATION
    • PHOSPHORYLATION
    • BINDING
    • FAMILY
    • ROLES
    • TAK1

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