Apoptosis: Death cycle and Swiss army knives

MICHAEL O. HENGARTNER

Cytochrome c leads a double life. When a cell is called on to commit apoptotic suicide, cytochrome c relocalizes from the mitochondria to the cytosol. There, it helps to activate the foot-soldiers of apoptosis — the death proteases known as caspases1. How cytochrome c escapes from the mitochondria is still a matter of debate1, but it is clear that certain elements within the apoptotic regulatory hierarchy do not condone such behaviour. In particular, overexpression of the cell-death suppressors Bcl-2 and Bcl-xL prevents the release of cytochrome c, suggesting that these proteins act upstream of cytochrome c in the pathway to cell death2,3. However, on pages 449 and 496 of this issue, Zhivotovsky et al.4 and Rossé et al.5 show that Bcl-2 can also protect cells downstream of cytochrome c release, forcing a re-evaluation of this newly acquired dogma.

Caspases do the brunt of the work in apoptosis. Activated through proteolytic processing, they cleave a limited number of apoptotic substrates and cause, directly or indirectly, most of the changes that are characteristic of apoptosis (for example, see ref. 6). So how are caspases activated? In the nematode worm Caenorhabditis elegans, the caspase homologue CED-3 is activated through a physical interaction between proCED-3 and CED-4. Interaction with CED-4 seems to be the only mechanism available for CED-3 activation, because there is no programmed cell death in ced-4 mutant animals. In cells that should survive, CED-9 (which belongs to the Bcl-2 family) binds to CED-4 and holds it in an inactive conformation, thereby preventing CED-4-mediated activation of proCED-3. The ability of CED-9, CED-4 and CED-3 to exist in a multiprotein complex has led to the ‘apoptosome’ model of cell-death regulation (reviewed in ref. 7).
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