title: A type III effector antagonizes death receptor signalling during bacterial gut infection.
abstract: Successful infection by enteric bacterial pathogens depends on the ability of the bacteria to colonize the gut, replicate in host tissues and disseminate to other hosts. Pathogens such as Salmonella, Shigella and enteropathogenic and enterohaemorrhagic (EPEC and EHEC, respectively) Escherichia coli use a type III secretion system (T3SS) to deliver virulence effector proteins into host cells during infection that promote colonization and interfere with antimicrobial host responses. Here we report that the T3SS effector NleB1 from EPEC binds to host cell death-domain-containing proteins and thereby inhibits death receptor signalling. Protein interaction studies identified FADD, TRADD and RIPK1 as binding partners of NleB1. NleB1 expressed ectopically or injected by the bacterial T3SS prevented Fas ligand or TNF-induced formation of the canonical death-inducing signalling complex (DISC) and proteolytic activation of caspase-8, an essential step in death-receptor-induced apoptosis. This inhibition depended on the N-acetylglucosamine transferase activity of NleB1, which specifically modified Arg 117 in the death domain of FADD. The importance of the death receptor apoptotic pathway to host defence was demonstrated using mice deficient in the FAS signalling pathway, which showed delayed clearance of the EPEC-like mouse pathogen Citrobacter rodentium and reversion to virulence of an nleB mutant. The activity of NleB suggests that EPEC and other attaching and effacing pathogens antagonize death-receptor-induced apoptosis of infected cells, thereby blocking a major antimicrobial host response.
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, Victoria 3010, Australia.
authors.forename: Jaclyn S
authors.initials: JS
authors.lastname: Pearson
authors.forename: Cristina
authors.initials: C
authors.lastname: Giogha
authors.forename: Sze Ying
authors.initials: SY
authors.lastname: Ong
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Kennedy
authors.forename: Michelle
authors.initials: M
authors.lastname: Kelly
authors.forename: Keith S
authors.initials: KS
authors.lastname: Robinson
authors.forename: Tania Wong Fok
authors.initials: TW
authors.lastname: Lung
authors.forename: Ashley
authors.initials: A
authors.lastname: Mansell
authors.forename: Patrice
authors.initials: P
authors.lastname: Riedmaier
authors.forename: Clare V L
authors.initials: CV
authors.lastname: Oates
authors.forename: Ali
authors.initials: A
authors.lastname: Zaid
authors.forename: Sabrina
authors.initials: S
authors.lastname: Mühlen
authors.forename: Valerie F
authors.initials: VF
authors.lastname: Crepin
authors.forename: Olivier
authors.initials: O
authors.lastname: Marches
authors.forename: Ching-Seng
authors.initials: CS
authors.lastname: Ang
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Williamson
authors.forename: Lorraine A
authors.initials: LA
authors.lastname: O'Reilly
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Bankovacki
authors.forename: Ueli
authors.initials: U
authors.lastname: Nachbur
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Infusini
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Webb
authors.forename: John
authors.initials: J
authors.lastname: Silke
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.forename: Gad
authors.initials: G
authors.lastname: Frankel
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Hartland
mesh_terms: D000818:Animals; D053181:Caspase 8 / Q000378:metabolism; D016923:Cell Death; D044082:Citrobacter rodentium / Q000472:pathogenicity / Q000502:physiology; D054308:Enteropathogenic Escherichia coli / Q000378:metabolism* / Q000472:pathogenicity; D004789:Enzyme Activation; D004927:Escherichia coli Infections / Q000378:metabolism* / Q000382:microbiology* / Q000473:pathology; D029968:Escherichia coli Proteins / Q000378:metabolism*; D053222:Fas Ligand Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein / Q000737:chemistry / Q000378:metabolism; D005260:Female; D041981:Gastrointestinal Tract / Q000382:microbiology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D053199:TNF Receptor-Associated Death Domain Protein / Q000737:chemistry / Q000378:metabolism; D037521:Virulence Factors / Q000378:metabolism*; D019014:fas Receptor / Q000172:deficiency / Q000378:metabolism
chemical_list: D029968:Escherichia coli Proteins; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; C553814:NleB protein, E coli; D053199:TNF Receptor-Associated Death Domain Protein; D037521:Virulence Factors; D019014:fas Receptor; D017351:N-Acetylglucosaminyltransferases; C063057:UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D053181:Caspase 8
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