The chains of death

Apoptosis is a highly conserved program of cell death in multicellular organisms that is central to their homeostasis. Defects in apoptosis are associated with cancer as well as neurodegenerative and autoimmune diseases. There are two ways apoptosis can be induced: intrinsic and extrinsic. The intrinsic pathway is triggered via changes in the mitochondria, the extrinsic pathway via stimulation of the so-called death receptors (DRs). All members of the DR family are expressed on the cell membrane and characterized by the presence of a death domain (DD) playing a central role in the transduction of the apoptotic signal. So far the DR family comprises TNF-R1, CD95/Fas/APO-1, DR3, TNFrelated apoptosis-inducing ligand-receptor (TRAIL-R1), TRAIL-R2 and DR6. The central event in DR signaling is the formation of the death-inducing signaling complex (DISC). The DISC comprises oligomerized, probably trimerized receptors, the adaptor protein FADD, procaspase-8, procaspase-10 and c-FLIP. Procaspase-8 activation at the DISC is a central initiation event in CD95induced apoptosis. The N-terminal part of procaspase-8 has two death effector domains (DED) followed by the large catalytic subunit p18 and a small catalytic subunit p10. Elegant biochemical studies have shown that procaspase-8 activation at the DISC involves dimerization, oligomerization and cleavage. The cleavage of procaspase-8 at the DISC occurs via several cleavage products, leading to the generation of the active caspase-8 heterotetramer p10 2 -p18 2 . Despite the fascinating progress in understanding caspase-8 activation at the DISC, several issues have remained open. The chains of death A new view on caspase-8 activation at the DISC