Control of NOD2 and Rip2-Dependent Innate Immune Activation by GEF-H1

Yun Zhao, Carmen Alonso, Isabel Ballester, Joo Hye Song, Sun Young Chang, Bayasi Guleng, Seiji Arihiro, Peter J. Murray, Ramnik Xavier, Koichi S. Kobayashi, Hans Christian Reinecker

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Background: Genetic variants of nucleotide-binding oligomerization domain 2 (NOD2) lead to aberrant microbial recognition and can cause chronic inflammatory diseases in patients with Crohn's disease (CD). Methods: We utilized gene-specific siRNA mediated knockdown and expression of guanine nucleotide exchange factor H1 (GEF-H1) in wild-type, Rip2-, and Nod2-deficient macrophages, HCT-116 and HEK 293 cells to determine the role of GEF-H1 in NOD2 and Rip2-mediated NFκB- dependent induction of proinflammatory cytokine expression. Confocal microscopy was used to determine subcellular distribution of GEFH1, Rip2, and NOD2. Results: We identified GEF-H1 as an unexpected component of innate immune regulation during microbial pattern recognition by NOD2. Surprisingly, GEF-H1-mediated the activation of Rip2 during signaling by NOD2, but not in the presence of the 3020insC variant of NOD2 associated with CD. GEF-H1 functioned downstream of NOD2 as part of Rip2-containing signaling complexes and was responsible for phosphorylation of Rip2 by Src tyrosine kinase. Rip2 variants lacking the tyrosine target of GEF-H1-mediated phosphorylation were unable to mediate NF-κB activation in Rip2-deficient macrophages and failed to transduce NOD2 signaling. GEF-H1 is required downstream of NOD2 as part of Rip2-containing signaling complexes for the activation of innate immune responses. Conclusions: GEF-H1 connects tyrosine kinase function to NOD-like receptor signaling and is fundamental to the regulation of microbial recognition by ubiquitous innate immune mechanisms mediated by Rip2 kinase.

Original languageEnglish (US)
Pages (from-to)603-612
Number of pages10
JournalInflammatory bowel diseases
Volume18
Issue number4
DOIs
StatePublished - Apr 2012
Externally publishedYes

Keywords

  • Crohn's disease
  • Innate immune regulation
  • NOD-like receptors
  • Src-kinase
  • Tyrosine phosphorylation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Gastroenterology

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