{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T21:30:50Z","timestamp":1774128650922,"version":"3.50.1"},"reference-count":35,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2018,3,1]],"date-time":"2018-03-01T00:00:00Z","timestamp":1519862400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Infect Immun"],"published-print":{"date-parts":[[2018,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            <jats:named-content content-type=\"genus-species\">Aggregatibacter actinomycetemcomitans<\/jats:named-content>\n            is an oral pathogen causing periodontal disease and bacterial endocarditis. It produces cytolethal distending toxin (CDT) that could damage mammalian cells and tissues. CDT is a tripartite protein toxin composed of CdtA, CdtB, and CdtC. We have previously indicated that CdtA is a lipoprotein and that the proteolytic processing of CdtA is important for biogenesis and secretion of CDT holotoxin. Here, we established an\n            <jats:italic>in vitro<\/jats:italic>\n            processing assay of CdtA and investigated the interactions of CdtA with other Cdt subunits. This assay demonstrated that incubation of membrane-bound CdtA (MCdtA), CdtB, and CdtC immediately generated a processed form of CdtA (CdtA\u2032), which is recovered from the soluble fraction. In contrast, incubation of soluble membrane-unbound CdtA with CdtB and CdtC did not yield any CdtA\u2032. Furthermore, incubation of CdtC with MCdtA was enough to induce rapid processing of MCdtA, whereas CdtB alone was unable to induce the processing. Coimmunoprecipitation demonstrated that CdtA\u2032 and CdtC formed a complex. Furthermore, subsequent addition of CdtB to this reaction mixture resulted in complete CDT holotoxin complex. The cytolethal distending activity assay demonstrated that CDT complex containing CdtA\u2032 showed far stronger cytotoxicity than that containing CdtA. Collectively, our data suggest that CDT holotoxin formation\n            <jats:italic>in vivo<\/jats:italic>\n            is a sequential event: interaction of MCdtA and CdtC induces proteolytic processing of MCdtA, and the released CdtA\u2032 forms a complex with CdtC. Subsequent binding of CdtB to the CdtA\u2032\/CdtC complex results in CDT holotoxin formation.\n          <\/jats:p>","DOI":"10.1128\/iai.00731-17","type":"journal-article","created":{"date-parts":[[2017,12,11]],"date-time":"2017-12-11T16:15:27Z","timestamp":1513008927000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":7,"title":["CdtC-Induced Processing of Membrane-Bound CdtA Is a Crucial Step in Aggregatibacter actinomycetemcomitans Cytolethal Distending Toxin Holotoxin Formation"],"prefix":"10.1128","volume":"86","author":[{"given":"Keiko","family":"Tsuruda","sequence":"first","affiliation":[{"name":"Department of Bacteriology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan"},{"name":"Department of Oral Health Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oranart","family":"Matangkasombut","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Research Unit on Oral Microbiology and Immunology, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand"},{"name":"Laboratory of Biotechnology, Chulabhorn Research Institute, Bangkok, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaru","family":"Ohara","sequence":"additional","affiliation":[{"name":"Hiroshima University Dental Clinic, Higashihiroshima, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9252-7739","authenticated-orcid":false,"given":"Motoyuki","family":"Sugai","sequence":"additional","affiliation":[{"name":"Department of Bacteriology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 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