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.