title: Pellino3 ubiquitinates RIP2 and mediates Nod2-induced signaling and protective effects in colitis.
abstract: Mutations that result in loss of function of Nod2, an intracellular receptor for bacterial peptidoglycan, are associated with Crohn's disease. Here we found that the E3 ubiquitin ligase Pellino3 was an important mediator in the Nod2 signaling pathway. Pellino3-deficient mice had less induction of cytokines after engagement of Nod2 and had exacerbated disease in various experimental models of colitis. Furthermore, expression of Pellino3 was lower in the colons of patients with Crohn's disease. Pellino3 directly bound to the kinase RIP2 and catalyzed its ubiquitination. Loss of Pellino3 led to attenuation of Nod2-induced ubiquitination of RIP2 and less activation of the transcription factor NF-κB and mitogen-activated protein kinases (MAPKs). Our findings identify RIP2 as a substrate for Pellino3 and Pellino3 as an important mediator in the Nod2 pathway and regulator of intestinal inflammation.
authors.affiliation: Institute of Immunology, Department of Biology, National University of Ireland Maynooth, Ireland.
authors.forename: Shuo
authors.initials: S
authors.lastname: Yang
authors.forename: Bingwei
authors.initials: B
authors.lastname: Wang
authors.forename: Fiachra
authors.initials: F
authors.lastname: Humphries
authors.forename: Ruaidhri
authors.initials: R
authors.lastname: Jackson
authors.forename: Marc E
authors.initials: ME
authors.lastname: Healy
authors.forename: Ronan
authors.initials: R
authors.lastname: Bergin
authors.forename: Gabriella
authors.initials: G
authors.lastname: Aviello
authors.forename: Barry
authors.initials: B
authors.lastname: Hall
authors.forename: Deirdre
authors.initials: D
authors.lastname: McNamara
authors.forename: Trevor
authors.initials: T
authors.lastname: Darby
authors.forename: Aoife
authors.initials: A
authors.lastname: Quinlan
authors.forename: Fergus
authors.initials: F
authors.lastname: Shanahan
authors.forename: Silvia
authors.initials: S
authors.lastname: Melgar
authors.forename: Padraic G
authors.initials: PG
authors.lastname: Fallon
authors.forename: Paul N
authors.initials: PN
authors.lastname: Moynagh
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D044082:Citrobacter rodentium / Q000276:immunology; D003092:Colitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination; D055815:Young Adult
chemical_list: D053473:Nod2 Signaling Adaptor Protein; C584081:PELI3 protein, mouse; D044767:Ubiquitin-Protein Ligases; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse
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