| Host S-nitrosylation inhibits clostridial small molecule-activated glucosylating toxins. | |
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MedLine Citation:
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PMID: 21857653 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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 |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-08-21 |
Journal Detail:
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Title: Nature medicine Volume: 17 ISSN: 1546-170X ISO Abbreviation: Nat. Med. Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-09-08 Completed Date: 2011-11-18 Revised Date: 2012-02-13 |
Medline Journal Info:
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Nlm Unique ID: 9502015 Medline TA: Nat Med Country: United States |
Other Details:
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Languages: eng Pagination: 1136-41 Citation Subset: IM |
Affiliation:
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Department of Gastroenterology & Hepatology, University of Texas Medical Branch, Galveston, Texas, USA. tcsavidg@utmb.edu |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Bacterial Toxins / chemistry, metabolism* Caco-2 Cells Clostridium Infections / drug therapy* Clostridium difficile / pathogenicity* Cysteine Proteases / metabolism Enterotoxins / chemistry, metabolism* Humans Ileum / microbiology, pathology Mice Models, Molecular* Nitric Oxide / metabolism Phytic Acid / metabolism Protein Conformation* S-Nitrosothiols / therapeutic use Statistics, Nonparametric Virulence |
| Grant Support | |
ID/Acronym/Agency:
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1UL1RR029876-01/RR/NCRR NIH HHS; K01DK076549/DK/NIDDK NIH HHS; N01-HV-00245/HV/NHLBI NIH HHS; N01AI30050/AI/NIAID NIH HHS; P01-HL075443-06A/HL/NHLBI NIH HHS; R01-HL059130/HL/NHLBI NIH HHS; R01-HL091876/HL/NHLBI NIH HHS; R01-HL095463/HL/NHLBI NIH HHS; R01AI088748/AI/NIAID NIH HHS; R01DK084509/DK/NIDDK NIH HHS; R21 DK078032-01A2/DK/NIDDK NIH HHS; R21 DK078032-02/DK/NIDDK NIH HHS; R21-DK078032-01/DK/NIDDK NIH HHS; UL1 RR029876-01/RR/NCRR NIH HHS; //Howard Hughes Medical Institute |
| Chemical | |
Reg. No./Substance:
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0/Bacterial Toxins; 0/Enterotoxins; 0/S-Nitrosothiols; 0/tcdA protein, Clostridium difficile; 10102-43-9/Nitric Oxide; 83-86-3/Phytic Acid; EC 3.4.-/Cysteine Proteases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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