Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis

The protein Bid is a participant in the pathway that leads to cell death (a poptosis), mediating the release of cytochrome c from mitochondria in respo nse to signals from 'death' receptors known as TNFR1/Fas on the cell surfac e(1-7). It is a member of the pro-apoptotic Bcl-2 familys and is activated as a result of its cleavage by caspase 8, one of a family of proteolytic ce ll-death proteins. To investigate the role of Bid in vivo, we have generate d mice deficient for Bid. We find that when these mice are injected with an antibody directed against Fas, they nearly all survive, whereas wild-type mice die from hepatocellular apoptosis and haemorrhagic necrosis. About hal f of the Bid-deficient animals had no apparent liver injury and showed no e vidence of activation of the effector caspases 3 and 7, although the initia tor caspase 8 had been activated. Other Bid-deficient mice survived with on ly moderate damage: all three caspases (8 and 37) were activated but their cell nuclei were intact and no mitochondrial cytochrome c was released. We also investigated the effects of Bid deficiency in cultured cells treated w ith anti-pas antibody (hepatocytes and thymocytes) or with TNF-alpha. (fibr oblasts). In these Bid(-/-) cells, mitochondrial dysfunction was delayed, c ytochrome c was not released, effector caspase activity was reduced and the cleavage of apoptosis substrates was altered. This loss-of-function model indicates that Bid is a critical substrate in vivo for signalling by death- receptor agonists, which mediates a mitochondrial amplification loop that i s essential for the apoptosis of selected cells.