Coordinated regulation of Toll-like receptor and NOD2 signaling by K63-linked polyubiquitin chains.
Mol Cell Biol
; 27(17): 6012-25, 2007 Sep.
Article
em En
| MEDLINE
| ID: mdl-17562858
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.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Poliubiquitina
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Peptídeos e Proteínas de Sinalização Intracelular
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Receptores Toll-Like
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Proteína Adaptadora de Sinalização NOD2
Limite:
Animals
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Humans
Idioma:
En
Revista:
Mol Cell Biol
Ano de publicação:
2007
Tipo de documento:
Article
País de afiliação:
Estados Unidos