GSBS Student Publications

Title

Coordinated regulation of Toll-like receptor and NOD2 signaling by K63-linked polyubiquitin chains

GSBS Program

Biochemistry & Molecular Pharmacology

Publication Date

2007-06-15

UMMS Affiliation

Graduate School of Biomedical Sciences; Department of Cancer Biology; Department of Molecular Genetics and Microbiology

Document Type

Article

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

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-kappaB 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-kappaB. 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 beta-activated kinase 1 [TAK1]/TAB/Ubc13) to activate NF-kappaB, 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.

DOI of Published Version

10.1128/MCB.00270-07

Source

Mol Cell Biol. 2007 Sep;27(17):6012-25. Epub 2007 Jun 11. Link to article on publisher's site

Journal/Book/Conference Title

Molecular and cellular biology

Related Resources

Link to article in PubMed

PubMed ID

17562858

Share

COinS