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

Shuo Yang, Bingwei Wang, Fiachra Humphries, Ruaidhri Jackson, Marc E Healy, Ronan Bergin, Gabriella Aviello, Barry Hall, Deirdre McNamara, Trevor Darby, Aoife Quinlan, Fergus Shanahan, Silvia Melgar, Padraic G Fallon, Paul N Moynagh

Research output: Contribution to journalArticlepeer-review

84 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)927-936
Number of pages10
JournalNature Immunology
Volume14
Issue number9
DOIs
Publication statusPublished - Sept 2013

Bibliographical note

We thank P.A. Barker and M. Saleh (McGill University) for Flag-tagged RIP2 and Nod2; M. Parkers and the Broad Institute for help and use of the Ricopili search tool; and G. Holleran for assistance in collecting biopsy samples from human subjects. Supported by Science Foundation Ireland (07/IN.1/B972 to P.N.M.; 10/IN.1/B3004 to P.G.F.; 02/CE/B124 and 07/CE/B1368 to F.S.; and funding for the Alimentary Pharmabiotic Centre as a Centre for Science, Engineering and Technology) and the Health Research Board of Ireland (PhD/2007/09).

Keywords

  • 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
  • Signal Transduction
  • Ubiquitin-Protein Ligases
  • Ubiquitination
  • Young Adult
  • Journal Article
  • Research Support, Non-U.S. Gov't

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