Editors' ChoiceHost-Pathogen Interactions

Arginine GlcNAcylation for Infection

Science Signaling  17 Sep 2013:
Vol. 6, Issue 293, pp. ec221
DOI: 10.1126/scisignal.2004726

Death domains were named because they are found in proteins that participate in cell death pathways, such as apoptosis. Various extracellular ligands trigger signaling pathways involving proteins with death domains, including the tumor necrosis factor receptor (TNFR) and the receptor Fas, along with their respective adaptor proteins TRADD and FADD. Both Li et al. and Pearson et al. identified a mechanism by which enteropathogenic Escherichia coli (EPEC) limited cell death of infected cells. The virulence protein NleB acted as an N-acetylglucosamine (GlcNAc) transferase for specific arginine residues in death domains in TRADD, FADD, TNFR1, and the kinase RIPK1. However, death domains of other adaptors, such as MyD88, that lack the conserved arginine were not GlcNAcylated. When the targeted Arg in TRADD was mutated or GlcNAcylated (by coexpression of the catalytically active NleB but not the catalytically inactive mutant), TRADD failed to oligomerize, activate NF-κB (nuclear factor κB) signaling, or mediate apoptosis in response to TNFR ligands. Experiments with either cells infected with wild-type or NleB-deficient bacteria or cells transfected with NleB or mutant versions that lacked catalytic activity showed that arginine GlcNAcylation was mediated by this type III effector protein. In vitro catalytic assays verified that NleB directly modified TRADD. Li et al. reported that gut colonization of mice by Citrobacter rodentium was reduced if the bacteria lacked NleB compared with colonization by wild-type bacteria. Pearson et al. also found reduced activation of caspase-8, an effector caspase in apoptosis, in the guts of mice infected with wild-type C. rodentium compared with that in mice infected with the NleB-deficient strain. Pearson et al. also examined infection in Fas-deficient mice and found that these mice developed diarrhea when infected with either the wild-type or NleB-deficient bacteria and had more severe tissue damage than infected wild-type mice. These results may be clinically relevant because some forms of colitis are associated with FasL polymorphisms. Thus, these two reports identify a previously unknown posttranslational modification—Arg GlcNAcylation—and also reveal the importance of specific Arg residues in mediating death domain oligomerization and initiation of downstream signaling in infected epithelial cells.

S. Li, L. Zhang, Q. Yao, L. Li, N. Dong, J. Rong, W. Gao, X. Ding, L. Sun, X. Chen, S. Chen, F. Shao, Pathogen blocks host death receptor signalling by arginine GlcNAcylation of death domains. Nature 501, 242–246 (2013). [PubMed]

J. S. Pearson, C. Goigha, S. Y. Ong, C. L. Kennedy, M. Kelly, K. S. Robinson, T. W. F. Lung, A. Mansell, P. Riedmaier, C. V. L. Oates, A. Zaid, S. Mühlen, V. F. Crepin, O. Marches, C.-S. Ang, N. A. Williamson, L. A. O’Reilly, A. Bankovacki, U. Nachbur, G. Infusini, A. I. Webb, J. Silke, A. Strasser, G. Frankel, E. L. Hartland, A type III effector antagonizes death receptor signalling during bacterial gut infection. Nature 501, 247–251 (2013). [PubMed]

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