Granzyme B: a natural born killer

Summary:  A main pathway used by cytotoxic T lymphocytes (CTLs) and natural killer cells to eliminate pathogenic cells is via exocytosis of granule components in the direction of the target cell, delivering a lethal hit of cytolytic molecules. Amongst these, granzyme B and perforin have been shown to induce CTL‐mediated target cell DNA fragmentation and apoptosis. Once released from the CTL, granzyme B binds its receptor, the mannose‐6‐phosphate/insulin‐like growth factor II receptor, and is endocytosed but remains arrested in endocytic vesicles until released by perforin. Once in the cytosol, granzyme B targets caspase‐3 directly or indirectly through the mitochondria, initiating the caspase cascade to DNA fragmentation and apoptosis. Caspase activity is required for apoptosis to occur; however, in the absence of caspase activity, granzyme B can still initiate mitochondrial events via the cleavage of Bid. Recent work shows that granzyme B‐mediated release of apoptotic factors from the mitochondria is essential for the full activation of caspase‐3. Thus, granzyme B acts at multiple points to initiate the death of the offending cell. Studies of the granzyme B death receptor and internal signaling pathways may lead to critical advances in cell transplantation and cancer therapy.