Truncated LKB1 nonenzymatically enhances Fas-induced apoptosis by acting as a surrogate of Smac.

IF 7 2区生物学 Q1 CELL BIOLOGY

Cell Death Discovery Pub Date : 2025-06-21 DOI:10.1038/s41420-025-02570-1

Yutaro Yamada, Mei Tsuchida, Takuya Noguchi, Takumi Yokosawa, Maki Mitsuya, Tatsuya Shimada, Daisuke Oikawa, Yusuke Hirata, Fuminori Tokunaga, Pascal Schneider, Atsushi Matsuzawa

{"title":"Truncated LKB1 nonenzymatically enhances Fas-induced apoptosis by acting as a surrogate of Smac.","authors":"Yutaro Yamada, Mei Tsuchida, Takuya Noguchi, Takumi Yokosawa, Maki Mitsuya, Tatsuya Shimada, Daisuke Oikawa, Yusuke Hirata, Fuminori Tokunaga, Pascal Schneider, Atsushi Matsuzawa","doi":"10.1038/s41420-025-02570-1","DOIUrl":null,"url":null,"abstract":"<p><p>Although liver kinase B1 (LKB1) has been established as a tumor suppressor kinase, its mechanism of action is incompletely understood. Here we describe a novel nonenzymatic function of LKB1 in cell death induced by Fas/CD95. In BID knockout HeLa cells, inactivation of mitochondrial outer membrane permeabilization (MOMP) prevents Smac-induced inhibition of X-linked inhibitor of apoptosis (XIAP), causing resistance to Fas-induced apoptosis. However, reexpression of LKB1 in those cells naturally deficient for endogenous LKB1 restored apoptosis. Mechanistically, caspase-8 activated by Fas processed LKB1 to a truncated form, tLKB1. Both WT and kinase-inactive LKB1 antagonized XIAP to restore apoptosis, but somatic mutants of LKB1 found in Peutz-Jeghers syndrome (PJS) failed to do so. Thus, in addition to the known caspase-8 / tBid / Smac / XIAP pro-apoptotic axis, our results unveil a novel one, caspase-8 / tLKB1 / XIAP that potentially contributes to the antitumor functions of LKB1.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"285"},"PeriodicalIF":7.0000,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12182575/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Death Discovery","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41420-025-02570-1","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Although liver kinase B1 (LKB1) has been established as a tumor suppressor kinase, its mechanism of action is incompletely understood. Here we describe a novel nonenzymatic function of LKB1 in cell death induced by Fas/CD95. In BID knockout HeLa cells, inactivation of mitochondrial outer membrane permeabilization (MOMP) prevents Smac-induced inhibition of X-linked inhibitor of apoptosis (XIAP), causing resistance to Fas-induced apoptosis. However, reexpression of LKB1 in those cells naturally deficient for endogenous LKB1 restored apoptosis. Mechanistically, caspase-8 activated by Fas processed LKB1 to a truncated form, tLKB1. Both WT and kinase-inactive LKB1 antagonized XIAP to restore apoptosis, but somatic mutants of LKB1 found in Peutz-Jeghers syndrome (PJS) failed to do so. Thus, in addition to the known caspase-8 / tBid / Smac / XIAP pro-apoptotic axis, our results unveil a novel one, caspase-8 / tLKB1 / XIAP that potentially contributes to the antitumor functions of LKB1.

查看原文本刊更多论文

截断的LKB1通过替代Smac非酶促fas诱导的细胞凋亡。

虽然肝激酶B1 （LKB1）已被确定为肿瘤抑制激酶，但其作用机制尚不完全清楚。在这里，我们描述了LKB1在Fas/CD95诱导的细胞死亡中的一种新的非酶功能。在BID敲除的HeLa细胞中，线粒体外膜透性（MOMP）失活可阻止smac诱导的X-linked inhibitor of apoptosis （XIAP）的抑制，从而对fas诱导的细胞凋亡产生抗性。然而，在那些自然缺乏内源性LKB1的细胞中，LKB1的重新表达恢复了细胞凋亡。从机制上讲，Fas激活的caspase-8将LKB1加工成截断形式tLKB1。WT和激酶失活的LKB1都能拮抗XIAP以恢复细胞凋亡，但在Peutz-Jeghers综合征（PJS）中发现的LKB1体细胞突变体却不能。因此，除了已知的促凋亡轴caspase-8 / tBid / Smac / XIAP外，我们的研究结果揭示了一个新的促凋亡轴caspase-8 / tLKB1 / XIAP，它可能有助于LKB1的抗肿瘤功能。

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

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.