title: GEF-H1 mediated control of NOD1 dependent NF-kappaB activation by Shigella effectors.
abstract: Shigella flexneri has evolved the ability to modify host cell function with intracellular active effectors to overcome the intestinal barrier. The detection of these microbial effectors and the initiation of innate immune responses are critical for rapid mucosal defense activation. The guanine nucleotide exchange factor H1 (GEF-H1) mediates RhoA activation required for cell invasion by the enteroinvasive pathogen Shigella flexneri. Surprisingly, GEF-H1 is requisite for NF-kappaB activation in response to Shigella infection. GEF-H1 interacts with NOD1 and is required for RIP2 dependent NF-kappaB activation by H-Ala-D-gammaGlu-DAP (gammaTriDAP). GEF-H1 is essential for NF-kappaB activation by the Shigella effectors IpgB2 and OspB, which were found to signal in a NOD1 and RhoA Kinase (ROCK) dependent manner. Our results demonstrate that GEF-H1 is a critical component of cellular defenses forming an intracellular sensing system with NOD1 for the detection of microbial effectors during cell invasion by pathogens.
authors.affiliation: Department of Medicine, Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Fukazawa
authors.forename: Carmen
authors.initials: C
authors.lastname: Alonso
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Kurachi
authors.forename: Sonal
authors.initials: S
authors.lastname: Gupta
authors.forename: Cammie F
authors.initials: CF
authors.lastname: Lesser
authors.forename: Beth Ann
authors.initials: BA
authors.lastname: McCormick
authors.forename: Hans-Christian
authors.initials: HC
authors.lastname: Reinecker
mesh_terms: D000818:Animals; D002460:Cell Line; D004285:Dogs; D004405:Dysentery, Bacillary / Q000209:etiology / Q000276:immunology; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D053474:Nod1 Signaling Adaptor Protein / Q000378:metabolism* / Q000502:physiology; D064067:Rho Guanine Nucleotide Exchange Factors; D012763:Shigella flexneri / Q000472:pathogenicity*; D020830:rac1 GTP-Binding Protein / Q000502:physiology
chemical_list: C577356:ARHGEF2 protein, human; D020662:Guanine Nucleotide Exchange Factors; D016328:NF-kappa B; C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein; D064067:Rho Guanine Nucleotide Exchange Factors; C508202:IpgB2 protein, Shigella flexneri; D020830:rac1 GTP-Binding Protein