Truncated LKB1 nonenzymatically enhances Fas-induced apoptosis by acting as a surrogate of Smac
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.
Authors
- Masayasu Mitsuya
- Takumi Yokosawa (ORCID: https://orcid.org/0009-0000-8695-3213)
- Mei Tsuchida
- Atsushi Matsuzawa (ORCID: https://orcid.org/0000-0001-8303-3905)
- Pascal Schneider (ORCID: https://orcid.org/0000-0003-0677-9409)
- Daisuke Oikawa
- Yutaro Yamada (ORCID: https://orcid.org/0000-0002-7895-7684)
- Yusuke Hirata (ORCID: https://orcid.org/0000-0002-1428-2075)
- Fuminori Tokunaga (ORCID: https://orcid.org/0000-0003-3626-9119)
- Takuya Noguchi (ORCID: https://orcid.org/0000-0001-6187-6645)
- Tatsuya Shimada (ORCID: https://orcid.org/0000-0001-6757-7590)
Institutions
- Gunma University (JP)
- Iwate Medical University (JP)
- Tohoku University (JP)
- Osaka Metropolitan University (JP)
- Tohoku Medical and Pharmaceutical University (JP)
- University of Lausanne (CH)
Publication Details
- Journal
- Cell Death Discovery
- Published
- 2025-06-21
- DOI
- https://doi.org/10.1038/s41420-025-02570-1
- Citations
- 1
- Primary Topic
- Cell death mechanisms and regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- National Science Foundation
- Ministry of Education, Culture, Sports, Science and Technology
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- nccr – on the move
- Japan Society for the Promotion of Science
- Institute for Molecular and Cellular Regulation, Gunma University