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Mol. Cell. Biol. doi:10.1128/MCB.02098-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Lys (K)63-linked polyubiquitination of IRAK-1 is required for IL-1 receptor- and Toll-like receptor-mediated NF-B activation

Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, 75235, USA

^* To whom correspondence should be addressed. Email: jda{at}pop.nci.nih.gov.

	Abstract

Stimulation through the IL-1 receptor (IL-1R) and some Toll-like receptors (TLRs) induces ubiquitination of TRAF6 and IRAK-1, signaling components required for NF- B and MAP kinase activation. Here we show that although TRAF6 and IRAK-1 acquired Lys (K)63-linked polyubiquitin chains upon IL-1 stimulation, only ubiquitinated IRAK-1 bound NEMO, the regulatory subunit of IB kinase (IKK). The sites of IRAK-1 ubiquitination were mapped to Lys134 and Lys180, and arginine substitution of these residues impaired IL-1R/TLR-mediated IRAK-1 ubiquitination, NEMO binding, and NF-B activation. K63-linked ubiquitination of IRAK-1 required enzymatically active TRAF6, indicating that it is the physiologically relevant E3. Thus, K63-linked polyubiquitination of proximal signaling proteins is a common mechanism used by diverse innate immune receptors for recruiting IKK and activating NF-B.

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