Clostridium difficile toxin CDT hijacks microtubule organization and reroutes vesicle traffic to increase pathogen adherence
Clostridium difficile causes antibiotic-associated diarrhea and pseudomembranous colitis by the actions of Rho-glucosylating toxins A and B. Recently identified hypervirulent strains, which are associated with increased morbidity and mortality, additionally produce the actin-ADP–ribosylating toxin C...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2014-02, Vol.111 (6), p.2313-2318 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Schwan, Carsten Kruppke, Anna S. Nölke, Thilo Schumacher, Lucas Koch-Nolte, Friedrich Kudryashev, Mikhail Stahlberg, Henning Aktories, Klaus |
| description | Clostridium difficile causes antibiotic-associated diarrhea and pseudomembranous colitis by the actions of Rho-glucosylating toxins A and B. Recently identified hypervirulent strains, which are associated with increased morbidity and mortality, additionally produce the actin-ADP–ribosylating toxin C. difficile transferase (CDT). CDT depolymerizes actin, causes formation of microtubule-based protrusions, and increases pathogen adherence. Here we show that CDT-induced protrusions allow vesicle traffic and contain endoplasmic reticulum tubules, connected to microtubules via the calcium sensor Stim1. The toxin reroutes Rab11-positive vesicles containing fibronectin, which is involved in bacterial adherence, from basolateral to the apical membrane sides in a microtubule- and Stim1-dependent manner. The data yield a model of C. difficile adherence regulated by actin depolymerization, microtubule restructuring, subsequent Stim1-dependent Ca ²⁺ signaling, vesicle rerouting, and secretion of ECM proteins to increase bacterial adherence. |
| doi_str_mv | 10.1073/pnas.1311589111 |
| format | Article |
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Recently identified hypervirulent strains, which are associated with increased morbidity and mortality, additionally produce the actin-ADP–ribosylating toxin C. difficile transferase (CDT). CDT depolymerizes actin, causes formation of microtubule-based protrusions, and increases pathogen adherence. Here we show that CDT-induced protrusions allow vesicle traffic and contain endoplasmic reticulum tubules, connected to microtubules via the calcium sensor Stim1. The toxin reroutes Rab11-positive vesicles containing fibronectin, which is involved in bacterial adherence, from basolateral to the apical membrane sides in a microtubule- and Stim1-dependent manner. The data yield a model of C. difficile adherence regulated by actin depolymerization, microtubule restructuring, subsequent Stim1-dependent Ca ²⁺ signaling, vesicle rerouting, and secretion of ECM proteins to increase bacterial adherence.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1311589111</identifier><identifier>PMID: 24469807</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>actin ; Actins ; Antibiotics ; Bacterial Adhesion ; Bacterial Toxins - toxicity ; Biological Sciences ; Biological Transport ; Caco 2 cells ; Calcium ; Calcium Signaling ; Cell membranes ; Clostridium difficile ; Clostridium difficile - metabolism ; Clostridium difficile - pathogenicity ; colitis ; depolymerization ; diarrhea ; endoplasmic reticulum ; Endoplasmic Reticulum - drug effects ; Enterotoxins - toxicity ; Epithelial cells ; fibronectins ; Fibronectins - metabolism ; Gram-positive bacteria ; Humans ; Microtubules ; Microtubules - drug effects ; morbidity ; mortality ; pathogens ; physiological transport ; Proteins ; Quantification ; Secretion ; Toxins</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2014-02, Vol.111 (6), p.2313-2318</ispartof><rights>copyright © 1993–2008 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Feb 11, 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c556t-6fcd0b070ffc84ef0136a8dd24a6c641060e2bf6922390a6d7955ba7bda18b93</citedby><cites>FETCH-LOGICAL-c556t-6fcd0b070ffc84ef0136a8dd24a6c641060e2bf6922390a6d7955ba7bda18b93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/111/6.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/23768859$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/23768859$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27903,27904,53769,53771,57995,58228</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24469807$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Schwan, Carsten</creatorcontrib><creatorcontrib>Kruppke, Anna S.</creatorcontrib><creatorcontrib>Nölke, Thilo</creatorcontrib><creatorcontrib>Schumacher, Lucas</creatorcontrib><creatorcontrib>Koch-Nolte, Friedrich</creatorcontrib><creatorcontrib>Kudryashev, Mikhail</creatorcontrib><creatorcontrib>Stahlberg, Henning</creatorcontrib><creatorcontrib>Aktories, Klaus</creatorcontrib><title>Clostridium difficile toxin CDT hijacks microtubule organization and reroutes vesicle traffic to increase pathogen adherence</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Clostridium difficile causes antibiotic-associated diarrhea and pseudomembranous colitis by the actions of Rho-glucosylating toxins A and B. Recently identified hypervirulent strains, which are associated with increased morbidity and mortality, additionally produce the actin-ADP–ribosylating toxin C. difficile transferase (CDT). CDT depolymerizes actin, causes formation of microtubule-based protrusions, and increases pathogen adherence. Here we show that CDT-induced protrusions allow vesicle traffic and contain endoplasmic reticulum tubules, connected to microtubules via the calcium sensor Stim1. The toxin reroutes Rab11-positive vesicles containing fibronectin, which is involved in bacterial adherence, from basolateral to the apical membrane sides in a microtubule- and Stim1-dependent manner. The data yield a model of C. difficile adherence regulated by actin depolymerization, microtubule restructuring, subsequent Stim1-dependent Ca ²⁺ signaling, vesicle rerouting, and secretion of ECM proteins to increase bacterial adherence.</description><subject>actin</subject><subject>Actins</subject><subject>Antibiotics</subject><subject>Bacterial Adhesion</subject><subject>Bacterial Toxins - toxicity</subject><subject>Biological Sciences</subject><subject>Biological Transport</subject><subject>Caco 2 cells</subject><subject>Calcium</subject><subject>Calcium Signaling</subject><subject>Cell membranes</subject><subject>Clostridium difficile</subject><subject>Clostridium difficile - metabolism</subject><subject>Clostridium difficile - pathogenicity</subject><subject>colitis</subject><subject>depolymerization</subject><subject>diarrhea</subject><subject>endoplasmic reticulum</subject><subject>Endoplasmic Reticulum - drug effects</subject><subject>Enterotoxins - toxicity</subject><subject>Epithelial cells</subject><subject>fibronectins</subject><subject>Fibronectins - metabolism</subject><subject>Gram-positive bacteria</subject><subject>Humans</subject><subject>Microtubules</subject><subject>Microtubules - drug effects</subject><subject>morbidity</subject><subject>mortality</subject><subject>pathogens</subject><subject>physiological transport</subject><subject>Proteins</subject><subject>Quantification</subject><subject>Secretion</subject><subject>Toxins</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkktv1DAUhSMEokNhzQqI1A2btPf6FXtTCU15SZVYMKwtx3FmPGTswU4qQPx4Ek2ZFjasvDjfOT6-vkXxHOEcoaYX-2DyOVJELhUiPigWCAorwRQ8LBYApK4kI-ykeJLzFgAUl_C4OCGMCSWhXhS_ln3MQ_KtH3dl67vOW9-7cojffSiXV6ty47fGfs3lztsUh7EZJzWmtQn-pxl8DKUJbZlciuPgcnnjsrezP5k5asopfbDJmezKvRk2ce0mR7txyQXrnhaPOtNn9-z2PC1W796ulh-q60_vPy7fXFeWczFUorMtNFBD11nJXAdIhZFtS5gRVjAEAY40nVCEUAVGtLXivDF10xqUjaKnxeUhdj82O9daF6Z6vd4nvzPph47G67-V4Dd6HW80VUQAq6eA17cBKX4bXR70zmfr-t4EF8esUQIFBajk_1GOhBJWs7nW2T_oNo4pTIPQyJQCzkHMd18cqGn8OSfXHXsj6HkH9LwD-m4HJsfL-8898n8-_R4wO49xiFpoQpFOwIsDsM1DTHcBtBZS8rn5q4PemajNOvmsv3wmgAIAGYDg9Deq7szG</recordid><startdate>20140211</startdate><enddate>20140211</enddate><creator>Schwan, Carsten</creator><creator>Kruppke, Anna S.</creator><creator>Nölke, Thilo</creator><creator>Schumacher, Lucas</creator><creator>Koch-Nolte, Friedrich</creator><creator>Kudryashev, Mikhail</creator><creator>Stahlberg, Henning</creator><creator>Aktories, Klaus</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7S9</scope><scope>L.6</scope><scope>5PM</scope></search><sort><creationdate>20140211</creationdate><title>Clostridium difficile toxin CDT hijacks microtubule organization and reroutes vesicle traffic to increase pathogen adherence</title><author>Schwan, Carsten ; 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Recently identified hypervirulent strains, which are associated with increased morbidity and mortality, additionally produce the actin-ADP–ribosylating toxin C. difficile transferase (CDT). CDT depolymerizes actin, causes formation of microtubule-based protrusions, and increases pathogen adherence. Here we show that CDT-induced protrusions allow vesicle traffic and contain endoplasmic reticulum tubules, connected to microtubules via the calcium sensor Stim1. The toxin reroutes Rab11-positive vesicles containing fibronectin, which is involved in bacterial adherence, from basolateral to the apical membrane sides in a microtubule- and Stim1-dependent manner. The data yield a model of C. difficile adherence regulated by actin depolymerization, microtubule restructuring, subsequent Stim1-dependent Ca ²⁺ signaling, vesicle rerouting, and secretion of ECM proteins to increase bacterial adherence.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>24469807</pmid><doi>10.1073/pnas.1311589111</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | actin Actins Antibiotics Bacterial Adhesion Bacterial Toxins - toxicity Biological Sciences Biological Transport Caco 2 cells Calcium Calcium Signaling Cell membranes Clostridium difficile Clostridium difficile - metabolism Clostridium difficile - pathogenicity colitis depolymerization diarrhea endoplasmic reticulum Endoplasmic Reticulum - drug effects Enterotoxins - toxicity Epithelial cells fibronectins Fibronectins - metabolism Gram-positive bacteria Humans Microtubules Microtubules - drug effects morbidity mortality pathogens physiological transport Proteins Quantification Secretion Toxins |
| title | Clostridium difficile toxin CDT hijacks microtubule organization and reroutes vesicle traffic to increase pathogen adherence |
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