title: Citrobacter rodentium NleB Protein Inhibits Tumor Necrosis Factor (TNF) Receptor-associated Factor 3 (TRAF3) Ubiquitination to Reduce Host Type I Interferon Production.
abstract: Interferon signaling plays important roles in both intestinal homeostasis and in the host response to pathogen infection. The extent to which bacterial pathogens inhibit this host pathway is an understudied area of investigation. We characterized Citrobacter rodentium strains bearing deletions in individual type III secretion system effector genes to determine whether this pathogen inhibits the host type I IFN response and which effector is responsible. The NleB effector limited host IFN-β production by inhibiting Lys(63)-linked ubiquitination of TNF receptor-associated factor 3 (TRAF3). Inhibition was dependent on the glycosyltransferase activity of NleB. GAPDH, a target of NleB during infection, bound to TRAF3 and was required for maximal TRAF3 ubiquitination. NleB glycosyltransferase activity inhibited GAPDH-TRAF3 binding, resulting in reduced TRAF3 ubiquitination. Collectively, our data reveal important interplay between GAPDH and TRAF3 and suggest a mechanism by which the NleB effector inhibits type I IFN signaling.
authors.affiliation: From the Whitehead Institute, Cambridge, Massachusetts 02142.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Gao
authors.affiliation: Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Thanh H
authors.initials: TH
authors.lastname: Pham
authors.affiliation: the College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506.
authors.forename: Leigh Ann
authors.initials: LA
authors.lastname: Feuerbacher
authors.affiliation: the College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506.
authors.forename: Kangming
authors.initials: K
authors.lastname: Chen
authors.affiliation: the College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hays
authors.affiliation: the National Institute of Occupational Health, Meghani Nagar, Ahmedabad 380016, Gujarat, India.
authors.forename: Gyanendra
authors.initials: G
authors.lastname: Singh
authors.affiliation: the Institute of Infectiology, University of Münster, D-48149 Münster, Germany, and.
authors.forename: Christian
authors.initials: C
authors.lastname: Rueter
authors.affiliation: the Fundacion ARAID, Edificio CEEI ARAGÓN and Institute of Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, BIFI-IQFR (CSIC) Joint Unit, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D, 50018 Zaragoza, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Hurtado-Guerrero
authors.affiliation: the College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506, hardwidg@vet.k-state.edu.
authors.forename: Philip R
authors.initials: PR
authors.lastname: Hardwidge
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D044082:Citrobacter rodentium / Q000201:enzymology / Q000235:genetics / Q000472:pathogenicity; D004756:Enterobacteriaceae Infections / Q000201:enzymology / Q000235:genetics; D016695:Glycosyltransferases / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism*; D054875:Ubiquitination; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D007370:Interferon Type I; D048008:TNF Receptor-Associated Factor 3; D037521:Virulence Factors; D016695:Glycosyltransferases
keywords: bacterial pathogenesis; infection; innate immunity; interferon; signal transduction