The IRAK-catalysed activation of the E3 ligase function of Pellino isoforms induces the Lys(63)-linked polyubiquitination of IRAK1

Alban Ordureau, Hilary Smith, Mark Windheim, Mark Peggie, Emma Carrick, Nick Morrice, Philip Cohen (Lead / Corresponding author)

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    126 Citations (Scopus)

    Abstract

    The protein kinases IRAK [IL-1 (interleukin 1) receptor-associated kinase] 1 and 4 play key roles in a signalling pathway by which bacterial infection or IL-1 trigger the production of inflammatory mediators. In the present study, we demonstrate that IRAK1 and IRAK4 phosphorylate Pellino isoforms in vitro and that phosphorylation greatly enhances Pellino's E3 ubiquitin ligase activity. We show that, in vitro, Pellino 1 can combine with the E2 conjugating complex Ubc13 (ubiquitin-conjugating enzyme 13)-Uev1 a (ubiquitin E2 variant la) to catalyse the formation of K63-pUb (Lys(63)-linked polyubiquitin) chains, with UbcH3 to catalyse the formation of K48-pUb chains and with UbcH4, UbcH5a or UbcH5b to catalyse the formation of pUb-chains linked mainly via Lys(11) and Lys(48) of ubiquitin. In IRAK1(-/-) cells, the co-transfection of DNA encoding wild-type IRAK1 and Pellino 2, but not inactive mutants of these proteins, induces the formation of K63-pUb-IRAK1 and its interaction with the NEMO [NF-kappa B (nuclear factor kappa B) essential modifier] regulatory subunit of the IKK (inhibitor of NF-kappa B kinase) complex, a K63-pUb-binding protein. These studies suggest that Pellino isoforms may be the E3 ubiquitin ligases that mediate the IL-1-stimulated formation of K63-pUb-IRAK1 in cells, which may contribute to the activation of IKK beta and the transcription factor NF-kappa B, as well as other signalling pathways dependent on IRAK 1/4.

    Original languageEnglish
    Pages (from-to)43-52
    Number of pages10
    JournalBiochemical Journal
    Volume409
    Issue number1
    DOIs
    Publication statusPublished - 2008

    Keywords

    • E3 ligase
    • inflammation
    • interleukin-1
    • interleukin 1 receptor-associated kinase (IRAK)
    • Pellino
    • ubiquitin
    • ubiquitin-conjugating enzyme 13 (Ubc13)
    • RECEPTOR-ASSOCIATED KINASE
    • NF-KAPPA-B
    • INTERLEUKIN-1 RECEPTOR
    • SIGNALING PATHWAYS
    • CRYSTAL-STRUCTURES
    • IMMUNE-RESPONSES
    • MICE LACKING
    • C-JUN
    • PROTEIN
    • COMPLEX

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