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PMID: 19043560 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

GEF-H1 mediated control of NOD1 dependent NF-kappaB activation by Shigella effectors.

PLoS pathogens ·Vol. 4 ·No. 11 ·2008-11-00 ·Pages e1000228

Fukazawa A, Alonso C, Kurachi K, Gupta S, Lesser CF, McCormick BA, Reinecker HC

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.

MeSH Terms
Animals Cell Line Dogs Dysentery, Bacillary/etiology,immunology Guanine Nucleotide Exchange Factors/metabolism,physiology Humans NF-kappa B/metabolism Nod1 Signaling Adaptor Protein/metabolism,physiology Rho Guanine Nucleotide Exchange Factors Shigella flexneri/pathogenicity rac1 GTP-Binding Protein/physiology
Chemicals
ARHGEF2 protein, human Guanine Nucleotide Exchange Factors NF-kappa B NOD1 protein, human Nod1 Signaling Adaptor Protein Rho Guanine Nucleotide Exchange Factors IpgB2 protein, Shigella flexneri rac1 GTP-Binding Protein
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Fukazawa Atsuko
Department of Medicine, Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Alonso Carmen
Kurachi Kiyotaka
Gupta Sonal
Lesser Cammie F
McCormick Beth Ann
Reinecker Hans-Christian
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Article Info
Journal
PLoS pathogens
Abbr.
PLoS Pathog
ISSN
1553-7374
DOI
10.1371/journal.ppat.1000228
Published
2008-11-00
Epub
2008-00-28
Pages
e1000228
Language
English
Region
United States
NLM ID
101238921
PMCID
PMC2583055
Subset
IM
Grants
NIDDK NIH HHS · R01 DK056754 · United States
NIDDK NIH HHS · R01 DK068181 · United States
NIAID NIH HHS · R01 AI064285 · United States
NIDDK NIH HHS · DK56754 · United States
NIDDK NIH HHS · P01 DK003506-20 · United States
External Links
PubMed source DOI: 10.1371/journal.ppat.1000228 PMC Full Text View journal details
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