Pellino3 ubiquitinates RIP2 and mediates Nod2-induced signaling and protective effects in colitis

Yang S, Wang B, Humphries F, Jackson R, Healy ME, Bergin R, Aviello G, Hall B, McNamara D, Darby T, Quinlan A, Shanahan F, Melgar S, Fallon PG, Moynagh PN

Nat Immunol. 2013 Sep;14(9):927-36. doi: 10.1038/ni.2669. Epub 2013 Jul 28.

Paul Moynagh, PhD, National University of Ireland, Maynooth

Paul Moynagh, PhD, National University of Ireland, Maynooth

This manuscript discovers a new role for the E3 ubiquitin ligase Pellino3 as a mediator of NOD2 signalling and as a potential regulator of inflammatory bowel diseases, especially Crohn’s disease. Loss of function mutations in NOD2 are associated with greatly increased susceptibility to Crohn’s disease suggesting that NOD2 plays a key protective role in regulating intestinal inflammation. RIP2 kinase is the most proximal signalling molecule in the NOD2 pathway and the ubiquitination of RIP2, in response to NOD2 stimulation, is essential to trigger downstream signalling and gene expression. In this manuscript we identify Pellino3 as the critical E3 ubiquitin ligase that ubiquitinates RIP2 in response to NOD2 stimulation thus mediating downstream signalling and ensuring homeostatic control of intestinal inflammation. This demonstrates that Pellino3 is a key mediator of the protective effects of NOD2 in colitis. This is further corroborated by the greatly reduced levels of Pellino3 in colon samples from Crohn’s disease patients. Pellino3 thus emerges as a novel regulator of innate immunity in the gut mucosal system. PMID:23892723