The anti-apoptotic Bcl-2 family members are induced by stimuli that promote cell survival. The best known of the anti-apoptotic proteins is Bcl-2 itself. The Bcl2 gene was first identified as an oncogene in a B-cell lymphoma, and its overexpression in tumors makes the cells more resistant to apoptotic stimuli and thus more likely to progress to an invasive cancer. Other members of the inhibitory family include Bcl-XL and Bcl-W. Anti-apoptotic proteins function by binding to the mitochondrial membrane to block the release of cytochrome c. The precise mechanism of inhibition is not clear, but they may function by directly blocking the function of the pro-apoptotic family members.
A second family of pro-apoptotic Bcl-2 family members are termed 'sentinels' and are activated by apoptotic stimuli. Once activated, these proteins, which include Bad, Bid, and PUMA, can either act to block the activity of the antiapoptotic proteins or act directly to stimulate the activity of the executioner pro-apoptotic proteins.
9-31 Cytotoxic effector proteins that trigger apoptosis are contained in the granules of CD8 cytotoxic T cells.
The principal mechanism of cytotoxic T-cell action is the calcium-dependent release of specialized cytotoxic granules upon recognition of antigen on the surface of a target cell. Cytotoxic granules are modified lysosomes that contain at least three distinct classes of cytotoxic effector proteins that are expressed specifically in cytotoxic T cells: perforin, granzymes, and granulysin (Fig. 9.44). These proteins are stored in cytotoxic granules in an active form, but conditions within the granules prevent their actions until after release. Perforin acts by forming pores in, or perforating, the target-cell plasma membrane, which both causes direct damage to the target cell and forms a conduit through which other contents of cytotoxic granules are delivered into the cytosol of the target cell. Granzymes, of which there are 5 in humans and 10 in the mouse, activate apoptosis once delivered to the target-cell cytosol via pores formed by perforin. Granulysin, which is expressed in humans but not in mice, has antimicrobial activity and at high concentrations is also able to induce apoptosis in target cells. Cytotoxic granules also contain the proteoglycan serglycin, which acts as a scaffold, forming a complex with perforin and the granzymes.
Both perforin and granzymes are required for effective target-cell killing. In cytotoxic cells that lack granzymes, the presence of perforin alone can kill target cells, but large numbers of cytotoxic cells are needed because the killing is very inefficient. In contrast, cytotoxic T cells from mice lacking perforin are unable to kill other cells, due to the lack of a mechanism to deliver granzymes into the target cell.