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Molecular and Cellular Biology, May 2008, p. 3538-3547, Vol. 28, No. 10
0270-7306/08/$08.00+0     doi:10.1128/MCB.02098-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Lys63-Linked Polyubiquitination of IRAK-1 Is Required for Interleukin-1 Receptor- and Toll-Like Receptor-Mediated NF-{kappa}B Activation{triangledown} ,{dagger}

Dietrich B. Conze,1 Chuan-Jin Wu,1 James A. Thomas,2 Allison Landstrom,1 and Jonathan D. Ashwell1*

Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892,1 Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 752352

Received 23 November 2007/ Returned for modification 28 December 2007/ Accepted 10 March 2008

Stimulation through the interleukin-1 receptor (IL-1R) and some Toll-like receptors (TLRs) induces ubiquitination of TRAF6 and IRAK-1, signaling components required for NF-{kappa}B and mitogen-activated protein kinase activation. Here we show that although TRAF6 and IRAK-1 acquired Lys63 (K63)-linked polyubiquitin chains upon IL-1 stimulation, only ubiquitinated IRAK-1 bound NEMO, the regulatory subunit of I{kappa}B 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-{kappa}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-{kappa}B.


* Corresponding author. Mailing address: Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892. Phone: (301) 496-4931. Fax: (301) 402-4844. E-mail: jda{at}pop.nci.nih.gov

{triangledown} Published ahead of print on 17 March 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.


Molecular and Cellular Biology, May 2008, p. 3538-3547, Vol. 28, No. 10
0270-7306/08/$08.00+0     doi:10.1128/MCB.02098-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.







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