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http://purl.uniprot.org/citations/21887730http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/21887730http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/21887730http://www.w3.org/2000/01/rdf-schema#comment"

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 wildtype, Rip2-, and Nod2-deficient macrophages, HCT-116 and HEK 293 cells to determine the role of GEF-H1 in NOD2 and Rip2-mediated NF-κB-dependent induction of proinflammatory cytokine expression. Confocal microscopy was used to determine subcellular distribution of GEF-H1, 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 3020 insC 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."xsd:string
http://purl.uniprot.org/citations/21887730http://purl.org/dc/terms/identifier"doi:10.1002/ibd.21851"xsd:string
http://purl.uniprot.org/citations/21887730http://purl.org/dc/terms/identifier"doi:10.1002/ibd.21851"xsd:string
http://purl.uniprot.org/citations/21887730http://purl.uniprot.org/core/author"Alonso C."xsd:string
http://purl.uniprot.org/citations/21887730http://purl.uniprot.org/core/author"Alonso C."xsd:string
http://purl.uniprot.org/citations/21887730http://purl.uniprot.org/core/author"Zhao Y."xsd:string
http://purl.uniprot.org/citations/21887730http://purl.uniprot.org/core/author"Zhao Y."xsd:string
http://purl.uniprot.org/citations/21887730http://purl.uniprot.org/core/author"Chang S.Y."xsd:string
http://purl.uniprot.org/citations/21887730http://purl.uniprot.org/core/author"Chang S.Y."xsd:string
http://purl.uniprot.org/citations/21887730http://purl.uniprot.org/core/author"Xavier R."xsd:string
http://purl.uniprot.org/citations/21887730http://purl.uniprot.org/core/author"Xavier R."xsd:string
http://purl.uniprot.org/citations/21887730http://purl.uniprot.org/core/author"Song J.H."xsd:string
http://purl.uniprot.org/citations/21887730http://purl.uniprot.org/core/author"Song J.H."xsd:string
http://purl.uniprot.org/citations/21887730http://purl.uniprot.org/core/author"Reinecker H.C."xsd:string
http://purl.uniprot.org/citations/21887730http://purl.uniprot.org/core/author"Reinecker H.C."xsd:string
http://purl.uniprot.org/citations/21887730http://purl.uniprot.org/core/author"Arihiro S."xsd:string
http://purl.uniprot.org/citations/21887730http://purl.uniprot.org/core/author"Arihiro S."xsd:string
http://purl.uniprot.org/citations/21887730http://purl.uniprot.org/core/author"Ballester I."xsd:string
http://purl.uniprot.org/citations/21887730http://purl.uniprot.org/core/author"Ballester I."xsd:string
http://purl.uniprot.org/citations/21887730http://purl.uniprot.org/core/author"Guleng B."xsd:string
http://purl.uniprot.org/citations/21887730http://purl.uniprot.org/core/author"Guleng B."xsd:string
http://purl.uniprot.org/citations/21887730http://purl.uniprot.org/core/author"Kobayashi K.S."xsd:string
http://purl.uniprot.org/citations/21887730http://purl.uniprot.org/core/author"Kobayashi K.S."xsd:string
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