Pellino3 ubiquitinates RIP2 and mediates Nod2-induced signaling and protective effects in colitis
Copyright policy )Pellino3 ubiquitinates RIP2 and mediates Nod2-induced signaling and protective effects in colitis
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.
- Boston Children's Hospital United States
- Queen's University Belfast United Kingdom
- University Federico II of Naples Italy
- National Children’s Research Centre Ireland
- University College Cork Ireland
Crohn’s disease, Adult, Male, 570, Adolescent, Knockout, Ubiquitin-Protein Ligases, Immunology, Nod2 Signaling Adaptor Protein, Gene Expression, Young Adult, Mice, Adolescent; Adult; Aged; Aged, 80 and over; Animals; Citrobacter rodentium; Colitis; Crohn Disease; Disease Models, Animal; Female; Gene Expression; Humans; Male; Mice; Mice, Knockout; Middle Aged; Nod2 Signaling Adaptor Protein; Protein Binding; Protein Interaction Domains and Motifs; Receptor-Interacting Protein Serine-Threonine Kinases; Ubiquitin-Protein Ligases; Ubiquitination; Young Adult; Signal Transduction, Crohn Disease, Inflammation & Infection, Receptor-Interacting Protein Serine-Threonine Kinase 2, Immunology, Inflammation & Infection, 80 and over, Animals, Humans, Protein Interaction Domains and Motifs, Institute of Immunology, Biology, Aged, Aged, 80 and over, Mice, Knockout, Animal, Biomedical sciences, Ubiquitination, Middle Aged, Colitis, Disease Models, Animal, Receptor-Interacting Protein Serine-Threonine Kinases, Disease Models, Citrobacter rodentium, Female, Signal Transduction, Protein Binding
Crohn’s disease, Adult, Male, 570, Adolescent, Knockout, Ubiquitin-Protein Ligases, Immunology, Nod2 Signaling Adaptor Protein, Gene Expression, Young Adult, Mice, Adolescent; Adult; Aged; Aged, 80 and over; Animals; Citrobacter rodentium; Colitis; Crohn Disease; Disease Models, Animal; Female; Gene Expression; Humans; Male; Mice; Mice, Knockout; Middle Aged; Nod2 Signaling Adaptor Protein; Protein Binding; Protein Interaction Domains and Motifs; Receptor-Interacting Protein Serine-Threonine Kinases; Ubiquitin-Protein Ligases; Ubiquitination; Young Adult; Signal Transduction, Crohn Disease, Inflammation & Infection, Receptor-Interacting Protein Serine-Threonine Kinase 2, Immunology, Inflammation & Infection, 80 and over, Animals, Humans, Protein Interaction Domains and Motifs, Institute of Immunology, Biology, Aged, Aged, 80 and over, Mice, Knockout, Animal, Biomedical sciences, Ubiquitination, Middle Aged, Colitis, Disease Models, Animal, Receptor-Interacting Protein Serine-Threonine Kinases, Disease Models, Citrobacter rodentium, Female, Signal Transduction, Protein Binding
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