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Molecular and Cellular Biology, September 2007, p. 6012-6025, Vol. 27, No. 17
0270-7306/07/$08.00+0     doi:10.1128/MCB.00270-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Coordinated Regulation of Toll-Like Receptor and NOD2 Signaling by K63-Linked Polyubiquitin Chains ^,

Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio,¹ Division of Gastrointestinal Pathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts,² Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Hospital, Boston, Massachusetts,³ Department of Systems Biology, Harvard Medical School, Boston, Massachusetts,⁴ Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts⁵

Received 14 February 2007/ Returned for modification 5 April 2007/ Accepted 1 June 2007

K63 polyubiquitin chains spatially and temporally link innate immune signaling effectors such that cytokine release can be coordinated. Crohn's disease is a prototypical inflammatory disorder in which this process may be faulty as the major Crohn's disease-associated protein, NOD2 (nucleotide oligomerization domain 2), regulates the formation of K63-linked polyubiquitin chains on the I kappa kinase (IKK) scaffolding protein, NEMO (NF-B essential modifier). In this work, we study these K63-linked ubiquitin networks to begin to understand the biochemical basis for the signaling cross talk between extracellular pathogen Toll-like receptors (TLRs) and intracellular pathogen NOD receptors. This work shows that TLR signaling requires the same ubiquitination event on NEMO to properly signal through NF-B. This ubiquitination is partially accomplished through the E3 ubiquitin ligase TRAF6. TRAF6 is activated by NOD2, and this activation is lost with a major Crohn's disease-associated NOD2 allele, L1007insC. We further show that TRAF6 and NOD2/RIP2 share the same biochemical machinery (transforming growth factor ß-activated kinase 1 [TAK1]/TAB/Ubc13) to activate NF-B, allowing TLR signaling and NOD2 signaling to synergistically augment cytokine release. These findings suggest a biochemical mechanism for the faulty cytokine balance seen in Crohn's disease.

Published ahead of print on 11 June 2007.

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

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