Publication Date:
2013-09-13
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836246/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836246/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pearson, Jaclyn S -- Giogha, Cristina -- Ong, Sze Ying -- Kennedy, Catherine L -- Kelly, Michelle -- Robinson, Keith S -- Lung, Tania Wong Fok -- Mansell, Ashley -- Riedmaier, Patrice -- Oates, Clare V L -- Zaid, Ali -- Muhlen, Sabrina -- Crepin, Valerie F -- Marches, Olivier -- Ang, Ching-Seng -- Williamson, Nicholas A -- O'Reilly, Lorraine A -- Bankovacki, Aleksandra -- Nachbur, Ueli -- Infusini, Giuseppe -- Webb, Andrew I -- Silke, John -- Strasser, Andreas -- Frankel, Gad -- Hartland, Elizabeth L -- 090325/Wellcome Trust/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2013 Sep 12;501(7466):247-51. doi: 10.1038/nature12524.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology and Immunology, University of Melbourne, Victoria 3010, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24025841" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antigens, CD95/deficiency/metabolism
;
Caspase 8/metabolism
;
Cell Death
;
Citrobacter rodentium/pathogenicity/physiology
;
Enteropathogenic Escherichia coli/*metabolism/pathogenicity
;
Enzyme Activation
;
Escherichia coli Infections/*metabolism/*microbiology/pathology
;
Escherichia coli Proteins/*metabolism
;
Fas Ligand Protein/antagonists & inhibitors/metabolism
;
Fas-Associated Death Domain Protein/chemistry/metabolism
;
Female
;
Gastrointestinal Tract/*microbiology
;
HEK293 Cells
;
HeLa Cells
;
Humans
;
Male
;
Mice
;
N-Acetylglucosaminyltransferases/metabolism
;
Protein Structure, Tertiary
;
Receptor-Interacting Protein Serine-Threonine Kinases/chemistry/metabolism
;
*Signal Transduction
;
TNF Receptor-Associated Death Domain Protein/chemistry/metabolism
;
Virulence Factors/*metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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