Coordinated regulation of Toll-like receptor and NOD2 signaling by K63-linked polyubiquitin chains.
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.
Abbott
Derek W
DW
Department of Pathology, Case Western Reserve University School of Medicine, Room 5123 Wolstein Research Building, Cleveland, OH 44106, and Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. dwa4@case.edu
Yang
Yibin
Y
Hutti
Jessica E
JE
Madhavarapu
Swetha
S
Kelliher
Michelle A
MA
Cantley
Lewis C
LC
D000818:Animals; D003424:Crohn Disease / Q000276:immunology; D004789:Enzyme Activation; D017930:Genes, Reporter; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D025821:Polyubiquitin / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D016328:NF-kappa B; D053473:Nod2 Signaling Adaptor Protein; D034741:RNA, Small Interfering; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; D025821:Polyubiquitin; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2