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J Biol Chem. 2017 Oct 20;292(42):17337-17350. doi: 10.1074/jbc.M117.805036. Epub 2017 Aug 31.

The bacterial arginine glycosyltransferase effector NleB preferentially modifies Fas-associated death domain protein (FADD).

Author information

1
From the Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne 3000, Australia, nichollas.scott@unimelb.edu.au.
2
From the Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne 3000, Australia.
3
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Melbourne, Australia.
4
the Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia, and.
5
Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Victoria 3010, Australia.

Abstract

The inhibition of host innate immunity pathways is essential for the persistence of attaching and effacing pathogens such as enteropathogenic Escherichia coli (EPEC) and Citrobacter rodentium during mammalian infections. To subvert these pathways and suppress the antimicrobial response, attaching and effacing pathogens use type III secretion systems to introduce effectors targeting key signaling pathways in host cells. One such effector is the arginine glycosyltransferase NleB1 (NleBCR in C. rodentium) that modifies conserved arginine residues in death domain-containing host proteins with N-acetylglucosamine (GlcNAc), thereby blocking extrinsic apoptosis signaling. Ectopically expressed NleB1 modifies the host proteins Fas-associated via death domain (FADD), TNFRSF1A-associated via death domain (TRADD), and receptor-interacting serine/threonine protein kinase 1 (RIPK1). However, the full repertoire of arginine GlcNAcylation induced by pathogen-delivered NleB1 is unknown. Using an affinity proteomic approach for measuring arginine-GlcNAcylated glycopeptides, we assessed the global profile of arginine GlcNAcylation during ectopic expression of NleB1, EPEC infection in vitro, or C. rodentium infection in vivo NleB overexpression resulted in arginine GlcNAcylation of multiple host proteins. However, NleB delivery during EPEC and C. rodentium infection caused rapid and preferential modification of Arg117 in FADD. This FADD modification was extremely stable and insensitive to physiological temperatures, glycosidases, or host cell degradation. Despite its stability and effect on the inhibition of apoptosis, arginine GlcNAcylation did not elicit any proteomic changes, even in response to prolonged NleB1 expression. We conclude that, at normal levels of expression during bacterial infection, NleB1/NleBCR antagonizes death receptor-induced apoptosis of infected cells by modifying FADD in an irreversible manner.

KEYWORDS:

Escherichia coli (E. coli); bacterial effectors; glycosylation; innate immunity; pathogenesis; post-translational modification (PTM)

PMID:
28860194
PMCID:
PMC5655511
[Available on 2018-10-20]
DOI:
10.1074/jbc.M117.805036
[Indexed for MEDLINE]

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