title: NleB, a bacterial effector with glycosyltransferase activity, targets GAPDH function to inhibit NF-κB activation.
abstract: 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 interacts with the TNF receptor-associated factor 2 (TRAF2), a protein required for TNF-α-mediated NF-κB 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-κB 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-κB-dependent host innate immune responses.
authors: University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors: Xiaofei
authors: X
authors: Gao
authors: Xiaogang
authors: X
authors: Wang
authors: Thanh H
authors: TH
authors: Pham
authors: Leigh Ann
authors: LA
authors: Feuerbacher
authors: Marie-Luise
authors: ML
authors: Lubos
authors: Minzhao
authors: M
authors: Huang
authors: Rachel
authors: R
authors: Olsen
authors: Arcady
authors: A
authors: Mushegian
authors: Chad
authors: C
authors: Slawson
authors: Philip R
authors: PR
authors: Hardwidge
mesh_terms: D000818:Animals; D044082:Citrobacter rodentium / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity; D015536:Down-Regulation; D004756:Enterobacteriaceae Infections / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016695:Glycosyltransferases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology*; D011485:Protein Binding; D014774:Virulence
chemical_list: D016328:NF-kappa B; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D016695:Glycosyltransferases