This Article Full Text Full Text (PDF) Supplemental material Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Conze, D. B. Articles by Ashwell, J. D. Search for Related Content PubMed PubMed Citation Articles by Conze, D. B. Articles by Ashwell, J. D.

 Previous Article  |  Next Article 

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-B Activation ^,

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

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-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 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.

---

* 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

Published ahead of print on 17 March 2008.

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.

This article has been cited by other articles:

• Keating, S. E., Bowie, A. G. (2009). Role of Non-degradative Ubiquitination in Interleukin-1 and Toll-like Receptor Signaling. J. Biol. Chem. 284: 8211-8215 [Full Text]  
• Coornaert, B., Carpentier, I., Beyaert, R. (2009). A20: Central Gatekeeper in Inflammation and Immunity. J. Biol. Chem. 284: 8217-8221 [Abstract] [Full Text]  
• Smith, H., Peggie, M., Campbell, D. G., Vandermoere, F., Carrick, E., Cohen, P. (2009). Inaugural Article: Identification of the phosphorylation sites on the E3 ubiquitin ligase Pellino that are critical for activation by IRAK1 and IRAK4. Proc. Natl. Acad. Sci. USA 106: 4584-4590 [Abstract] [Full Text]  
• Lamothe, B., Campos, A. D., Webster, W. K., Gopinathan, A., Hur, L., Darnay, B. G. (2008). The RING Domain and First Zinc Finger of TRAF6 Coordinate Signaling by Interleukin-1, Lipopolysaccharide, and RANKL. J. Biol. Chem. 283: 24871-24880 [Abstract] [Full Text]