Coordinated regulation of Toll-like receptor and NOD2 signaling by K63-linked polyubiquitin chains
Biochemistry & Molecular Pharmacology
Graduate School of Biomedical Sciences; Department of Cancer Biology; Department of Molecular Genetics and Microbiology
Medical Subject Headings
Animals; Crohn Disease; Enzyme Activation; Genes, Reporter; Humans; Immunity, Natural; Intracellular Signaling Peptides and Proteins; Mice; Mice, Knockout; NF-kappa B; Nod2 Signaling Adaptor Protein; Polyubiquitin; RNA, Small Interfering; Receptor-Interacting Protein Serine-Threonine Kinase 2; Signal Transduction; TNF Receptor-Associated Factor 6; Toll-Like Receptors
Life Sciences | Medicine and Health Sciences
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.
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Citation: Mol Cell Biol. 2007 Sep;27(17):6012-25. Epub 2007 Jun 11. Link to article on publisher's site
Abbott, Derek W.; Yang, Yibin; Hutti, Jessica E.; Madhavarapu, Swetha; Kelliher, Michelle A.; and Cantley, Lewis C., "Coordinated regulation of Toll-like receptor and NOD2 signaling by K63-linked polyubiquitin chains" (2007). GSBS Student Publications. Paper 35.