biostudies-literatureYamada YMEXT | Japan Society for the Promotion of Science (JSPS)Swiss National Science FoundationSwiss National Science Foundation | nccr - on the move (National Center of Competence in Research - The Migration-Mobility Nexus)285https://www.ebi.ac.uk/biostudies/studies/S-EPMC12182575biostudies-literatureUnknown11(1)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 aCell death discoveryTruncated LKB1 nonenzymatically enhances Fas-induced apoptosis by acting as a surrogate of Smac.PMC12182575JP21H00268JP24KJ0428JP24K02237JP18J20440205196JP24K02173JP21H02691310030310030-205196JP21H02620Noguchi TTokunaga FMitsuya MYokosawa TShimada TYamada YSchneider PMatsuzawa AOikawa DHirata YTsuchida MfalseTruncated 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 a2025-01-01T00:00:00Z2025 Jun2026-05-29T14:29:03.789Z2026-04-08T05:03:55.864ZS-EPMC121825754054419010.1038/s41420-025-02570-1