Interleukin-1 (IL-1) induces the Lys63-linked polyubiquitination of IL-1 receptor-associated kinase 1 to facilitate NEMO binding and the activation of IkappaBalpha kinase

Molecular and Cellular Biology
Mark WindheimPhilip Cohen

Abstract

Interleukin 1 (IL-1) has been reported to stimulate the polyubiquitination and disappearance of IL-1 receptor-associated kinase 1 (IRAK1) within minutes. It has been thought that the polyubiquitin chains attached to IRAK1 are linked via Lys48 of ubiquitin, leading to its destruction by the proteasome and explaining the rapid IL-1-induced disappearance of IRAK1. In this paper, we demonstrate that IL-1 stimulates the formation of K63-pUb-IRAK1 and not K48-pUb-IRAK1 and that the IL-1-induced disappearance of IRAK1 is not blocked by inhibition of the proteasome. We also show that IL-1 triggers the interaction of K63-pUb-IRAK1 with NEMO, a regulatory subunit of the IkappaBalpha kinase (IKK) complex, but not with the NEMO[D311N] mutant that cannot bind K63-pUb chains. Moreover, unlike wild-type NEMO, the NEMO[D311N] mutant was unable to restore IL-1-stimulated NF-kappaB-dependent gene transcription to NEMO-deficient cells. Our data suggest a model in which the recruitment of the NEMO-IKK complex to K63-pUb-IRAK1 and the recruitment of the TAK1 complex to TRAF6 facilitate the TAK1-catalyzed activation of IKK by the TRAF6-IRAK1 complex.

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Citations

Apr 6, 2012·Immunologic Research·Marie Anne O'Donnell, Adrian T Ting
Mar 14, 2009·Chemical Reviews·Yu-Hsin ChiuZhijian J Chen
Dec 2, 2010·Cell Research·Edward W Harhaj, Vishva M Dixit
Dec 8, 2010·Cell Research·Siqi Liu, Zhijian J Chen
Aug 14, 2009·Nature·Zong-Ping XiaZhijian J Chen
May 21, 2008·Nature Immunology·Etienne Meylan, Jürg Tschopp
Jun 2, 2009·Nature Reviews. Drug Discovery·Matthias GaestelMichael Kracht
Aug 31, 2013·Nature Reviews. Molecular Cell Biology·Kristopher ClarkPhilip Cohen
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Mar 11, 2008·The Journal of Biological Chemistry·Hui XiaoXiaoxia Li
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