Death by an extrinsic pathway involving TRAIL relies on intrinsic, mitochondrial events to kill human cancer cells.
The road to cell death involves two distinct routes — the 'extrinsic' and 'intrinsic' pathways, which proceed through death receptors or through mitochondrial events, respectively (see Box 1 in review by Jesenberger and Jentsch on page 113). Although these pathways converge at the level of effector caspases, they are thought to be completely separate before that. However, a report by Xiangwei Wu and colleagues in Genes and Development now adds to the growing evidence for crosstalk between these two pathways. They have discovered that death by an extrinsic pathway involving TRAIL (TNF-related apoptosis-inducing ligand) relies on intrinsic, mitochondrial events to kill human cancer cells.
Wu and co-workers used cells lacking Bax — a component of the intrinsic pathway — to show that this protein is needed for TRAIL-induced apoptosis. Examination of Bax localization showed that, whereas Bax is found in the cytosol before treatment with TRAIL, Bax translocates to the mitochondria after TRAIL treatment. Addition of an inhibitor that blocks the TRAIL-mediated extrinsic pathway prevented the translocation of Bax, suggesting that this movement depends on the extrinsic pathway.
What's the effect of Bax's translocation to the mitochondria, and how does this link to the intrinsic signalling pathway? Wu and colleagues showed that the loss of Bax blocks the release of intrinsic signalling factors (namely cytochrome c and Smac/DIABLO) from the mitochondria. But whereas TRAIL-induced apoptosis could still occur without cytochrome c-mediated caspase activation, the liberation of Smac/DIABLO was crucial.
Smac/DIABLO binds to — and removes the inhibitory effect of — a protein called the X-chromosome-linked inhibitor of apoptosis (XIAP), which normally inhibits caspase activity and blocks cell death. So Wu and colleagues propose a model in which the TRAIL-mediated translocation of Bax allows the release of Smac/DIABLO from the mitochondria. This, in turn, lifts the anti-apoptotic effects of XIAP, and allows cell death to proceed.
Alison Mitchell
References
ORIGINAL RESEARCH PAPER Deng, Y. , Lin, Y. & Wu, X. TRAIL-induced apoptosis requires Bax-dependent mitochondrial release of Smac/DIABLO. Genes Dev.16, 33–45 (2002) | PubMed |
