Host S-nitrosylation inhibits clostridial small molecule–activated glucosylating toxins
| Autor: | Charalabos Pothoulakis, Kausar Ali, Hanping Feng, Tor C. Savidge, Michael J. Loeffelholz, Robert D. English, Alfredo G. Torres, Jonathan S. Stamler, Lianfa Shi, Bo Herman, Numan Oezguen, Raj Kumar, Alfred Hausladen, Weijia Nie, John E. Wiktorowicz, Vinay Acharya, Werner Braun, Petri Urvil, Iryna V Pinchuk, Aproteem Choudhury |
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| Rok vydání: | 2011 |
| Předmět: |
Models
Molecular Phytic Acid Protein Conformation Bacterial Toxins Virulence Enterotoxin Biology Nitric Oxide medicine.disease_cause Statistics Nonparametric Article General Biochemistry Genetics and Molecular Biology Microbiology Enterotoxins Mice chemistry.chemical_compound Cysteine Proteases Ileum medicine Animals Humans Inositol S-Nitrosothiols Innate immune system Clostridioides difficile Toxin Nitrosylation General Medicine S-Nitrosylation Cysteine protease chemistry Clostridium Infections Caco-2 Cells |
| Zdroj: | Nature Medicine. 17:1136-1141 |
| ISSN: | 1546-170X 1078-8956 |
| Popis: | The global prevalence of severe Clostridium difficile infection highlights the profound clinical significance of clostridial glucosylating toxins1–4. Virulence is dependent on the autoactivation of a toxin cysteine protease5–9, which is promoted by the allosteric cofactor inositol hexakisphosphate (InsP6)10–17. 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 proteins18,19. 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, InsP6- and inositol pyrophosphate (InsP7)-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 InsP6 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. |
| Databáze: | OpenAIRE |
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