Bid is cleaved by caspase-8 within a native complex on the mitochondrial membrane

Eyal Gottlieb (1) , Zachary Schug (1) , Francois Gonzalvez (1) , Frédéric Vaz (1) , Riekelt Houtkooper (1)

1 The Beatson Institute for Cancer Research

Caspase-8 stably inserts into the mitochondrial outer membrane during extrinsic apoptosis. Inhibition of caspase-8 enrichment on the mitochondria impairs caspase-8 activation and prevents apoptosis. However, the function of active caspase-8 on the mitochondrial membrane remains unknown. In this study, we have identified a native complex containing caspase-8 and BID on the mitochondrial membrane and showed that death receptor activation by Fas or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induced the cleavage of BID (tBID formation) within this complex. tBID then shifted to separate mitochondria-associated complexes which contained other BCL-2 family members, such as BAK and BCL-XL. We report that cells stabilize active caspase-8 on the mitochondria in order to specifically target mitochondria-associated BID and that BID cleavage on the mitochondria is essential for caspase-8-induced cytochrome c release. Our findings indicate that during extrinsic apoptosis, caspase-8 can specifically target BID where it is mostly needed, on the surface of mitochondria.

Mots clés: apoptosis; mitochondria; caspase-8; Bid; Fas

Eyal Gottlieb, Zachary Schug, Francois Gonzalvez, Frédéric Vaz, Riekelt Houtkooper. Bid is cleaved by caspase-8 within a native complex on the mitochondrial membrane. Cell Death and Differentiation, 2010, ⟨10.1038/cdd.2010.135⟩. ⟨hal-00592286⟩