The cell death machinery.

The death receptor pathway (left) is triggered by members of the death receptor superfamily such as CD95. Binding of CD95-L to its receptor induces trimerization of CD95 and formation of a death-inducing complex. This complex recruits, via the adaptor molecule FADD, multiple procaspase-8 molecules, resulting in caspase-8 activation. Caspase-8 activation can be blocked by recruitment of c-FLIP. The mitochondrial death pathway (right) is controlled by members of the Bcl-2 family, including the proapoptotic Bax and Bid proteins and the antiapoptotic Bcl-2 and Bcl-X_L proteins. Death stimuli induce the release of cytochrome c, AIF, Apaf-1, Smac/DIABLO, and possibly other factors from mitochondria. Cytochrome c associates with Apaf-1 and caspase-9 to form the apoptosome. The death receptor and mitochondrial pathways converge at the level of caspase-3 activation. Caspase-3 activation and activity is antagonized by the IAP proteins, which themselves are antagonized by the Smac/DIABLO protein released from mitochondria. Active caspase-3 activates downstream caspases, which results in cleavage of cellular substrates and apoptosis. Crosstalk between the death receptor and mitochondrial pathways is provided by Bid, a proapoptotic Bcl-2 family member. Caspase-8–mediated cleavage of Bid greatly increases its prodeath activity and results in its translocation to mitochondria, where it promotes cytochrome c exit.