Coordinated regulation of Toll-like receptor and NOD2 signaling by K63-linked polyubiquitin chains
Graduate School of Biomedical Sciences; Department of Cancer Biology; Department of Molecular Genetics and Microbiology
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.
DOI of Published Version
Mol Cell Biol. 2007 Sep;27(17):6012-25. Epub 2007 Jun 11. Link to article on publisher's site
Molecular and cellular biology
Abbott DW, Yang Y, Hutti JE, Madhavarapu S, Kelliher MA, Cantley LC. (2007). Coordinated regulation of Toll-like receptor and NOD2 signaling by K63-linked polyubiquitin chains. GSBS Student Publications. https://doi.org/10.1128/MCB.00270-07. Retrieved from https://escholarship.umassmed.edu/gsbs_sp/35