{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T06:58:40Z","timestamp":1764053920476,"version":"build-2065373602"},"reference-count":63,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,8,29]],"date-time":"2024-08-29T00:00:00Z","timestamp":1724889600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Research Program on Emerging and Re-emerging Infectious Diseases of the Japan Agency for Medical Research and Development (AMED)","award":["22fk0108611h0902","23fk01086h0903"],"award-info":[{"award-number":["22fk0108611h0902","23fk01086h0903"]}]},{"name":"Association for Research on Lactic Acid Bacteria","award":["22fk0108611h0902","23fk01086h0903"],"award-info":[{"award-number":["22fk0108611h0902","23fk01086h0903"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Vibrio cholerae is an important foodborne pathogen. Cholix cytotoxin (Cholix), produced by V. cholerae, is a novel eukaryotic elongation factor 2 (eEF2) adenosine diphosphate ribosyltransferase that causes host cell death by inhibiting protein synthesis. However, the role of Cholix in the infectious diseases caused by V. cholerae remains unclear. Some bacterial cytotoxins are carried by host extracellular vesicles (EVs) and transferred to other cells. In this study, we investigated the effects of EV inhibitors and EV-regulating proteins on Cholix-induced hepatocyte death. We observed that Cholix-induced cell death was significantly enhanced in the presence of EV inhibitors (e.g., dimethyl amiloride, and desipramine) and Rab27a-knockdown cells, but it did not involve a sphingomyelin-dependent pathway. RNA sequencing analysis revealed that desipramine, imipramine, and EV inhibitors promoted the Cholix-activated c-Jun NH2-terminal kinase (JNK) pathway. Furthermore, JNK inhibition decreased desipramine-enhanced Cholix-induced poly (ADP-ribose) polymerase (PARP) cleavage. In addition, suppression of Apaf-1 by small interfering RNA further enhanced Cholix-induced PARP cleavage by desipramine. We identified a novel function of desipramine in which the stimulated JNK pathway promoted a mitochondria-independent cell death pathway by Cholix.<\/jats:p>","DOI":"10.3390\/toxins16090380","type":"journal-article","created":{"date-parts":[[2024,8,29]],"date-time":"2024-08-29T03:40:39Z","timestamp":1724902839000},"page":"380","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Extracellular Vesicle Inhibitors Enhance Cholix-Induced Cell Death via Regulation of the JNK-Dependent Pathway"],"prefix":"10.3390","volume":"16","author":[{"given":"Kazuya","family":"Ozaki","sequence":"first","affiliation":[{"name":"Laboratory of Microbiology and Infection Control, Division of Biological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiyo","family":"Nagahara","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology and Infection Control, Division of Biological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asaka","family":"Kawamura","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology and Infection Control, Division of Biological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2631-318X","authenticated-orcid":false,"given":"Takashi","family":"Ohgita","sequence":"additional","affiliation":[{"name":"Center for Instrumental Analysis, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sachika","family":"Higashi","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology and Infection Control, Division of Biological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kohei","family":"Ogura","sequence":"additional","affiliation":[{"name":"Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroyasu","family":"Tsutsuki","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sunao","family":"Iyoda","sequence":"additional","affiliation":[{"name":"Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo 162-8640, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsushi","family":"Yokotani","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology and Infection Control, Division of Biological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan"},{"name":"Kyoto Biken Laboratories, Inc., Kyoto 611-0041, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshiyuki","family":"Yamaji","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan"},{"name":"Department of Microbiology and Immunology, Faculty of Pharmacy, Juntendo University, Chiba 279-0013, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joel","family":"Moss","sequence":"additional","affiliation":[{"name":"Clinical Care Medicine and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20824-0105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kinnosuke","family":"Yahiro","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology and Infection Control, Division of Biological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2757","DOI":"10.3390\/toxins7082757","article-title":"The father, son and Cholix toxin: The third member of the DT group mono-ADP-ribosyltransferase toxin family","volume":"7","author":"Lugo","year":"2015","journal-title":"Toxins"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"10671","DOI":"10.1074\/jbc.M710008200","article-title":"Cholix toxin, a novel ADP-ribosylating factor from Vibrio cholerae","volume":"283","author":"Jorgensen","year":"2008","journal-title":"J. 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