title: Distinct Roles of the Antiapoptotic Effectors NleB and NleF from Enteropathogenic Escherichia coli.
abstract: During infection, enteropathogenicEscherichia coli(EPEC) translocates effector proteins directly into the cytosol of infected enterocytes using a type III secretion system (T3SS). Once inside the host cell, these effector proteins subvert various immune signaling pathways, including death receptor-induced apoptosis. One such effector protein is the non-locus of enterocyte effacement (LEE)-encoded effector NleB1, which inhibits extrinsic apoptotic signaling via the FAS death receptor. NleB1 transfers a singleN-acetylglucosamine (GlcNAc) residue to Arg117in the death domain of Fas-associated protein with death domain (FADD) and inhibits FAS ligand (FasL)-stimulated caspase-8 cleavage. Another effector secreted by the T3SS is NleF. Previous studies have shown that NleF binds to and inhibits the activity of caspase-4, -8, and -9in vitroHere, we investigated a role for NleF in the inhibition of FAS signaling and apoptosis during EPEC infection. We show that NleF prevents the cleavage of caspase-8, caspase-3, and receptor-interacting serine/threonine protein kinase 1 (RIPK1) in response to FasL stimulation. When translocated into host cells by the T3SS or expressed ectopically, NleF also blocked FasL-induced cell death. Using the EPEC-like mouse pathogenCitrobacter rodentium, we found that NleB but not NleF contributed to colonization of mice in the intestine. Hence, despite their shared ability to block FasL/FAS signaling, NleB and NleF have distinct roles during infection.
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
authors.forename: Georgina L
authors.initials: GL
authors.lastname: Pollock
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
authors.forename: Clare V L
authors.initials: CVL
authors.lastname: Oates
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
authors.forename: Cristina
authors.initials: C
authors.lastname: Giogha
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
authors.forename: Tania
authors.initials: T
authors.lastname: Wong Fok Lung
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
authors.forename: Sze Ying
authors.initials: SY
authors.lastname: Ong
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
authors.forename: Jaclyn S
authors.initials: JS
authors.lastname: Pearson
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia hartland@unimelb.edu.au.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Hartland
mesh_terms: D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D000066630:Ectopic Gene Expression; D054308:Enteropathogenic Escherichia coli / Q000502:physiology*; D004927:Escherichia coli Infections / Q000378:metabolism* / Q000382:microbiology*; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism*; D053222:Fas Ligand Protein / Q000378:metabolism; D005816:Genetic Complementation Test; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D015398:Signal Transduction; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism
chemical_list: D029968:Escherichia coli Proteins; D053222:Fas Ligand Protein; C553814:NleB protein, E coli; C583422:NleF protein, E coli; D037521:Virulence Factors; D019014:fas Receptor; D020169:Caspases
keywords: EPEC; FasL signaling; NleB1; NleF; caspase inhibitor; cell death