{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T21:42:32Z","timestamp":1791322952768,"version":"4.3.1"},"reference-count":72,"publisher":"Portland Press Ltd.","issue":"13","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,7,1]]},"abstract":"<jats:p>Staphylococcus aureus is a leading cause of bacterial infections in humans, including life-threatening diseases such as pneumonia and sepsis. Its small membrane-pore-forming \u03b1-toxin is considered an important virulence factor. By destroying cell\u2013cell contacts through cleavage of cadherins, the metalloproteinase ADAM10 (a disintegrin and metalloproteinase 10) critically contributes to \u03b1-toxin-dependent pathology of experimental S. aureus infections in mice. Moreover, ADAM10 was proposed to be a receptor for \u03b1-toxin. However, it is unclear whether the catalytic activity or specific domains of ADAM10 are involved in mediating binding and\/or subsequent cytotoxicity of \u03b1-toxin. Also, it is not known how \u03b1-toxin triggers ADAM10\u2019s enzymatic activity, and whether ADAM10 is invariably required for all \u03b1-toxin action on cells. In the present study, we show that efficient cleavage of the ADAM10 substrate epithelial cadherin (E-cadherin) requires supra-cytotoxic concentrations of \u03b1-toxin, leading to significant increases in intracellular [Ca2+]; the fall in cellular ATP levels, typically following membrane perforation, became observable at far lower concentrations. Surprisingly, ADAM10 was dispensable for \u03b1-toxin-dependent xenophagic targeting of S. aureus, whereas a role for \u03b1-toxin attack on the plasma membrane was confirmed. The catalytic site of ADAM10, furin cleavage site, cysteine switch and intracellular domain of ADAM10 were not required for \u03b1-toxin binding and subsequent cytotoxicity. In contrast, an essential role for the disintegrin domain and the prodomain emerged. Thus, co-expression of the prodomain with prodomain-deficient ADAM10 reconstituted binding of \u03b1-toxin and susceptibility of ADAM10-deficient cells. The results of the present study may help to inform structural analyses of \u03b1-toxin\u2013ADAM10 interactions and to design novel strategies to counteract S. aureus \u03b1-toxin action.<\/jats:p>","DOI":"10.1042\/bcj20160062","type":"journal-article","created":{"date-parts":[[2016,5,5]],"date-time":"2016-05-05T04:48:59Z","timestamp":1462423739000},"page":"1929-1940","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Dissecting the role of ADAM10 as a mediator of <i>Staphylococcus aureus<\/i> \u03b1-toxin action"],"prefix":"10.1042","volume":"473","author":[{"given":"Gisela","family":"von Hoven","sequence":"first","affiliation":[{"name":"Institute of Medical Microbiology and Hygiene, University Medical Center, Johannes Gutenberg-University Mainz, Hochhaus am Augustusplatz, D-55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amable\u00a0J.","family":"Rivas","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology and Hygiene, University Medical Center, Johannes Gutenberg-University Mainz, Hochhaus am Augustusplatz, D-55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Neukirch","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology and Hygiene, University Medical Center, Johannes Gutenberg-University Mainz, Hochhaus am Augustusplatz, D-55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Klein","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology and Hygiene, University Medical Center, Johannes Gutenberg-University Mainz, Hochhaus am Augustusplatz, D-55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Hamm","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology and Hygiene, University Medical Center, Johannes Gutenberg-University Mainz, Hochhaus am Augustusplatz, D-55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Qin","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology and Hygiene, University Medical Center, Johannes Gutenberg-University Mainz, Hochhaus am Augustusplatz, D-55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Meyenburg","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology and Hygiene, University Medical Center, Johannes Gutenberg-University Mainz, Hochhaus am Augustusplatz, D-55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"F\u00fcser","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology and Hygiene, University Medical Center, Johannes Gutenberg-University Mainz, Hochhaus am Augustusplatz, D-55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Saftig","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, University of Kiel, Olshausenstra\u00dfe 40, D-24098 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadja","family":"Hellmann","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biophysics, Faculty of Biology, Johannes Gutenberg-University Mainz, Jakob Welder Weg 26, D-55128 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf","family":"Postina","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University Mainz, Johann-Joachim Becherweg 30, D-55128 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Husmann","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology and Hygiene, University Medical Center, Johannes Gutenberg-University Mainz, Hochhaus am Augustusplatz, D-55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2016,6,28]]},"reference":[{"key":"2021112216270227000_B1","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1128\/mr.55.4.733-751.1991","article-title":"Alpha-toxin of Staphylococcus aureus","volume":"55","author":"Bhakdi","year":"1991","journal-title":"Microbiol. 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