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

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

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

Cell Death Discov. 2025 Jun 21;11(1):285. doi: 10.1038/s41420-025-02570-1.

Authors

Yutaro Yamada^#¹, Mei Tsuchida^#¹, Takuya Noguchi^#^{2

3

4

5}, Takumi Yokosawa¹, Maki Mitsuya¹, Tatsuya Shimada¹, Daisuke Oikawa^{6

7}, Yusuke Hirata¹, Fuminori Tokunaga^{6

7}, Pascal Schneider⁸, Atsushi Matsuzawa⁹

Affiliations

¹ Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
² Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. noguctak@iwate-med.ac.jp.
³ Department of Medical Biochemistry, School of Pharmacy, Iwate Medical University, Yahaba, Japan. noguctak@iwate-med.ac.jp.
⁴ Department of Immunobiology, University of Lausanne, Epalinges, Switzerland. noguctak@iwate-med.ac.jp.
⁵ Laboratory of Molecular Cell Biology, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan. noguctak@iwate-med.ac.jp.
⁶ Laboratory of Molecular Cell Biology, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan.
⁷ Department of Medical Biochemistry, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan.
⁸ Department of Immunobiology, University of Lausanne, Epalinges, Switzerland.
⁹ Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. atsushi.matsuzawa.c6@tohoku.ac.jp.

^# Contributed equally.

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.

Abstract

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