Figure 3.

A schematic model of granzyme-B-mediated apoptosis. Granzyme B enters the target cell by endocytosis and leaves the endosomal compartment to access the cytosol in a perforin-dependent manner. The key cytosolic substrate for granzyme B is the pro-apoptotic Bcl-2 family member Bid, which is cleaved distal to aspartic acid at position 75. Truncated Bid (tBid) induces mitochondrial disruption, which can be inhibited by Bcl-2. Disrupted mitochondria release other pro-apoptotic mediators such as cytochrome c and DIABLO/Smac, which subsequently induce caspase activation. Granzyme B also cleaves some caspases directly, but full caspase processing requires activation of the mitochondrial pathway through Bid. There are also caspase-independent pathways to cell death, and although they are poorly characterized, an important step in these pathways appears to be cytoskeletal disruption.