K63 polyubiquitinated RIP2 associates with the TAK1 complex TAK1 is activated A20 deubiquitinates RIP2 CARD9 binds RIP2 (and NOD2) Activation of p38 MAPK TAK1 phosphorylates MKK6 NOD1 induced apoptosis is mediated by RIP2 and CARD8 iE-DAP elicits a NOD1 response RIP2 binds NEMO RIP2 induces K63-linked ubiquitination of NEMO CYLD deubiquitinates NEMO RIP2 is K63 polyubiquitinated MDP elicits a NOD2 response Activated NOD1 oligomerizes Activated NOD2 oligomerizes Activated NOD oligomer recruites RIP2 (RICK) PathwayStep6877 PathwayStep6876 PathwayStep6879 PathwayStep6878 PathwayStep6880 PathwayStep6869 PathwayStep6868 PathwayStep6867 PathwayStep6866 PathwayStep6865 PathwayStep6874 PathwayStep6875 PathwayStep6872 PathwayStep6873 PathwayStep6870 PathwayStep6871 NOD1/2 Signaling Pathway Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 GENE ONTOLOGYGO:0070423 NOD1 is ubiquitously expressed, while NOD2 expression is restricted to monocytes, macrophages, dendritic cells, and intestinal Paneth cells (Inohara et al. 2005). NOD1 and NOD2 activation induces transcription of immune response genes, predominantly mediated by the proinflammatory transcriptional factor NFkappaB but also by AP-1 and Elk-1 (Inohara et al. 2005). NFkappaB translocates to the nucleus following release from IkappaB proteins. NOD1 and NOD2 signaling involves an interaction between their caspase-recruitment domain (CARD) and the CARD of the kinase RIPK2 (RIP2/RICK). This leads to the activation of the NFkappaB pathway and MAPK pathways (Windheim et al. 2007).<br>Activated NODs oligomerize via their NACHT domains, inducing physical proximity of RIP2 proteins that is believed to trigger their K63-linked polyubiquitination, facilitating recruitment of the TAK1 complex. RIP2 also recruits NEMO, bringing the TAK1 and IKK complexes into proximity, leading to NF-kappaB activation and activation of MAPK signaling. Recent studies have demonstrated that K63-linked regulatory ubiquitination of RIP2 is essential for the recruitment of TAK1 (Hasegawa et al. 2008, Hitosumatsu et al. 2008). As observed for toll-like receptor (TLR) signaling, ubiquitination can be removed by the deubiquitinating enzyme A20, thereby dampening NOD1/NOD2-induced NF-kappaB activation. NOD1 and NOD2 both induce K63-linked ubiquitination of RIP2, but NOD2-signaling appears to preferentially utilize the E3 ligase TRAF6, while TRAF2 and TRAF5 were shown to be important for NOD1-mediated signaling. In both cases, activation of NF-kappaB results in the upregulated transcription and production of inflammatory mediators. Pubmed15952891 Pubmed17348859 Pubmed18079694 Pubmed18342009 Pubmed18414735 Pubmed18585455 Pubmed18928408 Reactome Database ID Release 43168638 Reactome, http://www.reactome.org ReactomeREACT_75776 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 PathwayStep3436 Activated TAK1 mediates phosphorylation of the IKK Complex