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NleB, a bacterial effector with glycosyltransferase activity, targets GAPDH function to inhibit NF-?B activation.


ABSTRACT: Modulation of NF-?B-dependent responses is critical to the success of attaching/effacing (A/E) human pathogenic E. coli (EPEC and EHEC) and the natural mouse pathogen Citrobacter rodentium. NleB, a highly conserved type III secretion system effector of A/E pathogens, suppresses NF-?B activation, but the underlying mechanisms are unknown. We identified the mammalian glycolysis enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as an NleB-interacting protein. Further, we discovered that GAPDH interacts with the TNF receptor-associated factor 2 (TRAF2), a protein required for TNF-?-mediated NF-?B activation, and regulates TRAF2 polyubiquitination. During infection, NleB functions as a translocated N-acetyl-D-glucosamine (O-GlcNAc) transferase that modifies GAPDH. NleB-mediated GAPDH O-GlcNAcylation disrupts the TRAF2-GAPDH interaction to suppress TRAF2 polyubiquitination and NF-?B activation. Eliminating NleB O-GlcNAcylation activity attenuates C. rodentium colonization of mice. These data identify GAPDH as a TRAF2 signaling cofactor and reveal a virulence strategy employed by A/E pathogens to inhibit NF-?B-dependent host innate immune responses.

SUBMITTER: Gao X 

PROVIDER: S-EPMC3553500 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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NleB, a bacterial effector with glycosyltransferase activity, targets GAPDH function to inhibit NF-κB activation.

Gao Xiaofei X   Wang Xiaogang X   Pham Thanh H TH   Feuerbacher Leigh Ann LA   Lubos Marie-Luise ML   Huang Minzhao M   Olsen Rachel R   Mushegian Arcady A   Slawson Chad C   Hardwidge Philip R PR  

Cell host & microbe 20130116 1


Modulation of NF-κB-dependent responses is critical to the success of attaching/effacing (A/E) human pathogenic E. coli (EPEC and EHEC) and the natural mouse pathogen Citrobacter rodentium. NleB, a highly conserved type III secretion system effector of A/E pathogens, suppresses NF-κB activation, but the underlying mechanisms are unknown. We identified the mammalian glycolysis enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as an NleB-interacting protein. Further, we discovered that GAPDH  ...[more]

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