Host S-nitrosylation inhibits clostridial small molecule-activated glucosylating toxins

Tor C. Savidge, Petri Urvil, Numan Oezguen, Kausar Ali, Aproteem Choudhury, Vinay Acharya, Irina Pinchuk, Alfredo G. Torres, Robert D. English, John E. Wiktorowicz, Michael Loeffelholz, Raj Kumar, Lianfa Shi, Weijia Nie, Werner Braun, Bo Herman, Alfred Hausladen, Hanping Feng, Jonathan S. Stamler, Charalabos Pothoulakis

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

The global prevalence of severe Clostridium difficile infection highlights the profound clinical significance of clostridial glucosylating toxins. Virulence is dependent on the autoactivation of a toxin cysteine protease, which is promoted by the allosteric cofactor inositol hexakisphosphate (InsP 6). Host mechanisms that protect against such exotoxins are poorly understood. It is increasingly appreciated that the pleiotropic functions attributed to nitric oxide (NO), including host immunity, are in large part mediated by S-nitrosylation of proteins. Here we show that C. difficile toxins are S-nitrosylated by the infected host and that S-nitrosylation attenuates virulence by inhibiting toxin self-cleavage and cell entry. Notably, InsP 6-and inositol pyrophosphate (InsP 7)-induced conformational changes in the toxin enabled host S-nitrosothiols to transnitrosylate the toxin catalytic cysteine, which forms part of a structurally conserved nitrosylation motif. Moreover, treatment with exogenous InsP 6 enhanced the therapeutic actions of oral S-nitrosothiols in mouse models of C. difficile infection. Allostery in bacterial proteins has thus been successfully exploited in the evolutionary development of nitrosothiol-based innate immunity and may provide an avenue to new therapeutic approaches.

Original languageEnglish (US)
Pages (from-to)1136-1142
Number of pages7
JournalNature Medicine
Volume17
Issue number9
DOIs
StatePublished - Sep 1 2011

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Savidge, T. C., Urvil, P., Oezguen, N., Ali, K., Choudhury, A., Acharya, V., Pinchuk, I., Torres, A. G., English, R. D., Wiktorowicz, J. E., Loeffelholz, M., Kumar, R., Shi, L., Nie, W., Braun, W., Herman, B., Hausladen, A., Feng, H., Stamler, J. S., & Pothoulakis, C. (2011). Host S-nitrosylation inhibits clostridial small molecule-activated glucosylating toxins. Nature Medicine, 17(9), 1136-1142. https://doi.org/10.1038/nm.2405