Journal
BIOCHEMICAL JOURNAL
Volume 409, Issue -, Pages 43-52Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20071365
Keywords
E3 ligase; inflammation; interleukin-1; interleukin 1 receptor-associated kinase (IRAK); Pellino; ubiquitin; ubiquitin-conjugating enzyme 13 (Ubc13)
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Funding
- MRC [MC_U127084348] Funding Source: UKRI
- Medical Research Council [MC_U127084348] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
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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.
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