6e66

Structural highlights

Function

NLEB1_ECO27 Protein-arginine N-acetylglucosaminyltransferase effector that disrupts TNF signaling in infected cells, including NF-kappa-B signaling, apoptosis and necroptosis (PubMed:20126447, PubMed:20485572, PubMed:22144899, PubMed:23955153, PubMed:24025841, PubMed:28138023, PubMed:28522607, PubMed:30979585). Acts by catalyzing the transfer of a single N-acetylglucosamine (GlcNAc) to a conserved arginine residue in the death domain of host proteins FADD, TRADD, FAS, TNFRSF1A/TNFR1, TNFRSF25/DR3 and RIPK1: arginine GlcNAcylation prevents homotypic/heterotypic death domain interactions and assembly of the oligomeric TNF-alpha receptor complex, thereby disrupting TNF signaling (PubMed:23955153, PubMed:24025841, PubMed:26883593, PubMed:28522607, PubMed:28860194, PubMed:30979585). Has preference for host FADD as substrate compared to other death domain-containing proteins (PubMed:28860194). Also acts on host proteins without a death domain: catalyzes arginine GlcNAcylation of HIF1A, thereby regulating host glucose metabolism (PubMed:30125331). Also displays intra-bacterial activity by mediating GlcNAcylation of glutathione synthetase GshB (PubMed:31974499). Catalyzes auto-GlcNAcylation, which is required for activity toward death domain-containing host target proteins (PubMed:32432056). Shows a higher enzymatic activity than NleB2 (PubMed:23955153).^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]}

References

1. ↑ Nadler C, Baruch K, Kobi S, Mills E, Haviv G, Farago M, Alkalay I, Bartfeld S, Meyer TF, Ben-Neriah Y, Rosenshine I. The type III secretion effector NleE inhibits NF-kappaB activation. PLoS Pathog. 2010 Jan 29;6(1):e1000743. PMID:20126447 doi:10.1371/journal.ppat.1000743
2. ↑ Newton HJ, Pearson JS, Badea L, Kelly M, Lucas M, Holloway G, Wagstaff KM, Dunstone MA, Sloan J, Whisstock JC, Kaper JB, Robins-Browne RM, Jans DA, Frankel G, Phillips AD, Coulson BS, Hartland EL. The type III effectors NleE and NleB from enteropathogenic E. coli and OspZ from Shigella block nuclear translocation of NF-kappaB p65. PLoS Pathog. 2010 May 13;6(5):e1000898. PMID:20485572 doi:10.1371/journal.ppat.1000898
3. ↑ Ruchaud-Sparagano MH, Mühlen S, Dean P, Kenny B. The enteropathogenic E. coli (EPEC) Tir effector inhibits NF-κB activity by targeting TNFα receptor-associated factors. PLoS Pathog. 2011 Dec;7(12):e1002414. PMID:22144899 doi:10.1371/journal.ppat.1002414
4. ↑ Li S, Zhang L, Yao Q, Li L, Dong N, Rong J, Gao W, Ding X, Sun L, Chen X, Chen S, Shao F. Pathogen blocks host death receptor signalling by arginine GlcNAcylation of death domains. Nature. 2013 Sep 12;501(7466):242-6. PMID:23955153 doi:10.1038/nature12436
5. ↑ Pearson JS, Giogha C, Ong SY, Kennedy CL, Kelly M, Robinson KS, Lung TW, Mansell A, Riedmaier P, Oates CV, Zaid A, Mühlen S, Crepin VF, Marches O, Ang CS, Williamson NA, O'Reilly LA, Bankovacki A, Nachbur U, Infusini G, Webb AI, Silke J, Strasser A, Frankel G, Hartland EL. A type III effector antagonizes death receptor signalling during bacterial gut infection. Nature. 2013 Sep 12;501(7466):247-51. PMID:24025841 doi:10.1038/nature12524
6. ↑ Wong Fok Lung T, Giogha C, Creuzburg K, Ong SY, Pollock GL, Zhang Y, Fung KY, Pearson JS, Hartland EL. Mutagenesis and Functional Analysis of the Bacterial Arginine Glycosyltransferase Effector NleB1 from Enteropathogenic Escherichia coli. Infect Immun. 2016 Apr 22;84(5):1346-1360. PMID:26883593 doi:10.1128/IAI.01523-15
7. ↑ Pollock GL, Oates CVL, Giogha C, Wong Fok Lung T, Ong SY, Pearson JS, Hartland EL. Distinct Roles of the Antiapoptotic Effectors NleB and NleF from Enteropathogenic Escherichia coli. Infect Immun. 2017 Mar 23;85(4):e01071-16. PMID:28138023 doi:10.1128/IAI.01071-16
8. ↑ El Qaidi S, Chen K, Halim A, Siukstaite L, Rueter C, Hurtado-Guerrero R, Clausen H, Hardwidge PR. NleB/SseK effectors from Citrobacter rodentium, Escherichia coli, and Salmonella enterica display distinct differences in host substrate specificity. J Biol Chem. 2017 Jul 7;292(27):11423-11430. PMID:28522607 doi:10.1074/jbc.M117.790675
9. ↑ Scott NE, Giogha C, Pollock GL, Kennedy CL, Webb AI, Williamson NA, Pearson JS, Hartland EL. The bacterial arginine glycosyltransferase effector NleB preferentially modifies Fas-associated death domain protein (FADD). J Biol Chem. 2017 Oct 20;292(42):17337-17350. PMID:28860194 doi:10.1074/jbc.M117.805036
10. ↑ Xu C, Liu X, Zha H, Fan S, Zhang D, Li S, Xiao W. A pathogen-derived effector modulates host glucose metabolism by arginine GlcNAcylation of HIF-1α protein. PLoS Pathog. 2018 Aug 20;14(8):e1007259. PMID:30125331 doi:10.1371/journal.ppat.1007259
11. ↑ Ding J, Pan X, Du L, Yao Q, Xue J, Yao H, Wang DC, Li S, Shao F. Structural and Functional Insights into Host Death Domains Inactivation by the Bacterial Arginine GlcNAcyltransferase Effector. Mol Cell. 2019 Apr 3. pii: S1097-2765(19)30232-1. doi:, 10.1016/j.molcel.2019.03.028. PMID:30979585 doi:http://dx.doi.org/10.1016/j.molcel.2019.03.028
12. ↑ El Qaidi S, Scott NE, Hays MP, Geisbrecht BV, Watkins S, Hardwidge PR. An intra-bacterial activity for a T3SS effector. Sci Rep. 2020 Jan 23;10(1):1073. PMID:31974499 doi:10.1038/s41598-020-58062-y
13. ↑ Xue J, Pan X, Peng T, Duan M, Du L, Zhuang X, Cai X, Yi X, Fu Y, Li S. Auto Arginine-GlcNAcylation Is Crucial for Bacterial Pathogens in Regulating Host Cell Death. Front Cell Infect Microbiol. 2020 May 5;10:197. PMID:32432056 doi:10.3389/fcimb.2020.00197
14. ↑ Ding J, Pan X, Du L, Yao Q, Xue J, Yao H, Wang DC, Li S, Shao F. Structural and Functional Insights into Host Death Domains Inactivation by the Bacterial Arginine GlcNAcyltransferase Effector. Mol Cell. 2019 Apr 3. pii: S1097-2765(19)30232-1. doi:, 10.1016/j.molcel.2019.03.028. PMID:30979585 doi:http://dx.doi.org/10.1016/j.molcel.2019.03.028