Extracellular Vesicle Inhibitors Enhance Cholix-Induced Cell Death via Regulation of the JNK-Dependent Pathway

IF 3.9 3区医学 Q2 FOOD SCIENCE & TECHNOLOGY

Toxins Pub Date : 2024-08-29 DOI:10.3390/toxins16090380

Kazuya Ozaki, Hiyo Nagahara, Asaka Kawamura, Takashi Ohgita, Sachika Higashi, Kohei Ogura, Hiroyasu Tsutsuki, Sunao Iyoda, Atsushi Yokotani, Toshiyuki Yamaji, Joel Moss, Kinnosuke Yahiro

{"title":"Extracellular Vesicle Inhibitors Enhance Cholix-Induced Cell Death via Regulation of the JNK-Dependent Pathway","authors":"Kazuya Ozaki, Hiyo Nagahara, Asaka Kawamura, Takashi Ohgita, Sachika Higashi, Kohei Ogura, Hiroyasu Tsutsuki, Sunao Iyoda, Atsushi Yokotani, Toshiyuki Yamaji, Joel Moss, Kinnosuke Yahiro","doi":"10.3390/toxins16090380","DOIUrl":null,"url":null,"abstract":"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.","PeriodicalId":23119,"journal":{"name":"Toxins","volume":"22 1","pages":""},"PeriodicalIF":3.9000,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Toxins","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3390/toxins16090380","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"FOOD SCIENCE & TECHNOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

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.

查看原文本刊更多论文

细胞外囊泡抑制剂通过调节 JNK 依赖性通路增强胆碱酯酶诱导的细胞死亡

霍乱弧菌是一种重要的食源性病原体。霍乱弧菌产生的 Cholix 细胞毒素（Cholix）是一种新型真核细胞延伸因子 2（eEF2）二磷酸腺苷核糖转移酶，可通过抑制蛋白质合成导致宿主细胞死亡。然而，Cholix 在霍乱弧菌引起的传染病中的作用仍不清楚。一些细菌细胞毒素由宿主胞外囊泡（EVs）携带并转移到其他细胞。在本研究中，我们研究了EV抑制剂和EV调节蛋白对Cholix诱导的肝细胞死亡的影响。我们观察到，在EV抑制剂（如二甲基氨苯蝶啶和地西泮）和Rab27a敲除细胞存在的情况下，Cholix诱导的细胞死亡明显增强，但这并不涉及鞘磷脂依赖途径。RNA 测序分析表明，地西泮、丙咪嗪和 EV 抑制剂促进了 Cholix 激活的 c-Jun NH2 端激酶（JNK）通路。此外，抑制 JNK 可减少去甲丙咪嗪增强的 Cholix 诱导的多（ADP-核糖）聚合酶（PARP）裂解。此外，通过小干扰 RNA 抑制 Apaf-1 进一步增强了去甲丙咪嗪诱导 Cholix 的 PARP 分裂。我们发现了去甲丙咪嗪的一种新功能，即刺激的 JNK 通路促进了 Cholix 的线粒体依赖性细胞死亡通路。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Toxins TOXICOLOGY-

CiteScore

7.50

自引率

16.70%

发文量

765

审稿时长

16.24 days

期刊介绍： Toxins (ISSN 2072-6651) is an international, peer-reviewed open access journal which provides an advanced forum for studies related to toxins and toxinology. It publishes reviews, regular research papers and short communications. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.