title: Pathogen blocks host death receptor signalling by arginine GlcNAcylation of death domains.
abstract: The tumour necrosis factor (TNF) family is crucial for immune homeostasis, cell death and inflammation. These cytokines are recognized by members of the TNF receptor (TNFR) family of death receptors, including TNFR1 and TNFR2, and FAS and TNF-related apoptosis-inducing ligand (TRAIL) receptors. Death receptor signalling requires death-domain-mediated homotypic/heterotypic interactions between the receptor and its downstream adaptors, including TNFR1-associated death domain protein (TRADD) and FAS-associated death domain protein (FADD). Here we discover that death domains in several proteins, including TRADD, FADD, RIPK1 and TNFR1, were directly inactivated by NleB, an enteropathogenic Escherichia coli (EPEC) type III secretion system effector known to inhibit host nuclear factor-κB (NF-κB) signalling. NleB contained an unprecedented N-acetylglucosamine (GlcNAc) transferase activity that specifically modified a conserved arginine in these death domains (Arg 235 in the TRADD death domain). NleB GlcNAcylation (the addition of GlcNAc onto a protein side chain) of death domains blocked homotypic/heterotypic death domain interactions and assembly of the oligomeric TNFR1 complex, thereby disrupting TNF signalling in EPEC-infected cells, including NF-κB signalling, apoptosis and necroptosis. Type-III-delivered NleB also blocked FAS ligand and TRAIL-induced cell death by preventing formation of a FADD-mediated death-inducing signalling complex (DISC). The arginine GlcNAc transferase activity of NleB was required for bacterial colonization in the mouse model of EPEC infection. The mechanism of action of NleB represents a new model by which bacteria counteract host defences, and also a previously unappreciated post-translational modification.
authors: College of Biological Sciences, China Agricultural University, Beijing 100094, China.
authors: Shan
authors: S
authors: Li
authors: Li
authors: L
authors: Zhang
authors: Qing
authors: Q
authors: Yao
authors: Lin
authors: L
authors: Li
authors: Na
authors: N
authors: Dong
authors: Jie
authors: J
authors: Rong
authors: Wenqing
authors: W
authors: Gao
authors: Xiaojun
authors: X
authors: Ding
authors: Liming
authors: L
authors: Sun
authors: Xing
authors: X
authors: Chen
authors: She
authors: S
authors: Chen
authors: Feng
authors: F
authors: Shao
mesh_terms: D000215:Acylation; D000818:Animals; D017209:Apoptosis; D001120:Arginine / Q000378:metabolism*; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D054308:Enteropathogenic Escherichia coli / Q000378:metabolism* / Q000472:pathogenicity; D004927:Escherichia coli Infections / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D029968:Escherichia coli Proteins / Q000378:metabolism*; D053200:Fas-Associated Death Domain Protein / Q000737:chemistry / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D053199:TNF Receptor-Associated Death Domain Protein / Q000737:chemistry* / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014774:Virulence; D037521:Virulence Factors / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism
chemical_list: D053418:Death Domain Receptor Signaling Adaptor Proteins; D029968:Escherichia coli Proteins; D053200:Fas-Associated Death Domain Protein; D046912:Multiprotein Complexes; D016328:NF-kappa B; C553814:NleB protein, E coli; D047888:Receptors, Tumor Necrosis Factor, Type I; D053199:TNF Receptor-Associated Death Domain Protein; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D037521:Virulence Factors; D019014:fas Receptor; D001120:Arginine; D017351:N-Acetylglucosaminyltransferases; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases
references: J Org Chem. 1967 Apr;32(4):1073-80
references: 6042145
references: Nat Immunol. 2008 Sep;9(9):1047-54
references: 18641653
references: Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16953-8
references: 17068130
references: PLoS Pathog. 2010 Dec 16;6(12):e1001231
references: 21187904
references: Science. 2010 Sep 3;329(5996):1215-8
references: 20688984
references: Annu Rev Immunol. 2007;25:561-86
references: 17201679
references: J Biol Chem. 2011 Feb 18;286(7):5100-7
references: 21148319
references: Cell. 2008 May 16;133(4):693-703
references: 18485876
references: Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13725-30
references: 19666608
references: J Infect Dis. 2006 Sep 15;194(6):819-27
references: 16941350
references: Annu Rev Biochem. 2008;77:521-55
references: 18518825
references: Cell. 2012 Jan 20;148(1-2):213-27
references: 22265413
references: Infect Immun. 2006 Apr;74(4):2328-37
references: 16552063
references: Trends Biochem Sci. 2011 Oct;36(10):541-52
references: 21798745
references: Nat Immunol. 2012 Nov;13(11):1063-71
references: 23001144
references: Cell. 1996 Jan 26;84(2):299-308
references: 8565075
references: Mol Microbiol. 2011 Apr;80(1):219-30
references: 21306441
references: Cell Host Microbe. 2013 Jan 16;13(1):87-99
references: 23332158
references: Sci STKE. 2005 Nov 29;2005(312):re13
references: 16317114
references: Can J Microbiol. 2010 Sep;56(9):739-47
references: 20921984
references: J Immunol. 2010 Oct 1;185(7):4118-27
references: 20833837
references: Science. 2007 Feb 16;315(5814):1000-3
references: 17303758
references: Nat Immunol. 2009 Apr;10(4):348-55
references: 19295631
references: Infect Immun. 2004 Sep;72(9):5115-25
references: 15322005
references: Nat Rev Immunol. 2003 Sep;3(9):745-56
references: 12949498
references: Proc Natl Acad Sci U S A. 2008 Aug 26;105(34):12429-34
references: 18719121
references: Biochim Biophys Acta. 2010 Feb;1800(2):134-43
references: 19647041
references: Nature. 2011 Dec 11;481(7380):204-8
references: 22158122
references: PLoS Pathog. 2010 Jan 29;6(1):e1000743
references: 20126447
references: Annu Rev Biochem. 2011;80:825-58
references: 21391816
references: PLoS Pathog. 2011 Dec;7(12):e1002414
references: 22144899
references: PLoS Pathog. 2010 May 13;6(5):e1000898
references: 20485572
references: Nat Immunol. 2008 Sep;9(9):1037-46
references: 18641654
references: Cell Host Microbe. 2010 Jul 22;8(1):44-54
references: 20638641
references: Nat Chem Biol. 2013 Feb;9(2):84-9
references: 23292651
references: EMBO J. 2011 Jan 5;30(1):221-31
references: 21113130
references: Cell. 2012 Jan 20;148(1-2):228-43
references: 22265414
references: FEBS Lett. 1995 Nov 27;376(1-2):61-4
references: 8521968