Coordinated regulation of toll-like receptor and NOD2 signaling by K63-linked polyubiquitin chains Academic Article uri icon


MeSH Major

  • Intracellular Signaling Peptides and Proteins
  • Nod2 Signaling Adaptor Protein
  • Polyubiquitin
  • Signal Transduction
  • Toll-Like Receptors


  • 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.

publication date

  • September 2007



  • Academic Article



  • eng

PubMed Central ID

  • PMC1952158

Digital Object Identifier (DOI)

  • 10.1128/MCB.00270-07

PubMed ID

  • 17562858

Additional Document Info

start page

  • 6012

end page

  • 25


  • 27


  • 17