Granzyme B-mediated apoptosis – the elephant and the blind men?

Cytotoxic cell granule-mediated apoptosis is a unique form of cell signaling that entails the intracellular delivery of granule-associated serine proteases (granzymes). Recent work has suggested that the cytotoxic cell secretes macrocomplexes consisting of multiple granzymes and Perforin (PFN) bound to a scaffold proteoglycan named serglycin.¹ Among the granule proteases, the mechanism of apoptosis induction would seem most straightforward for granzyme B (GrB). GrB has been reported to cleave numerous caspases in vitro (-3, -6, -7, -8 -9 and -10)² stimulating the notion that the protease is able to initiate death by activating multiple family members in vivo. To complicate matters, the granzyme might also kill by digesting structural and regulatory proteins.^3,4 Finally, GrB has been reported to initiate death through a mitochondria-centered pathway by cleaving the BH3-only proapoptotic Bcl-2 family member, Bid.^5,6,7,8,9,10 Together the results imply that the granzyme has a multifaceted potential to ensure target cell death through mechanisms that are: (1) caspase-driven, (2) BH3 protein-driven, and (3) due to cleavage of crucial cellular proteins. These observations, however, require reconciliation with the finding that Bcl-2 reproducibly inhibits GrB-mediated apoptosis as defined by loss of clonogenic potential in the target cells. Bcl-2 is predicted to protect against a mitochondrial assault, but defense against apoptosis initiated through caspases as well as digestion of cellular proteins is more difficult to comprehend.

Apoptosis induced by cytotoxic T cells (CTLs) was originally observed to be associated with proteolysis of procaspase-3.¹¹ It was not clear at the time whether the granzyme entered the target or engaged a transmembrane signal to activate a ‘caspase cascade’. Complicating matters, microinjection of rat GrB into target cells failed to induce cell death.¹² Although the cytosolic delivery of GrB was inferred by studies where the granzyme was delivered intracellularly with adenoviral particles,¹³ this critical issue was eventually clarified by microinjection of the more active human form by the Bleackley and Froelich labs.

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