Mechanisms of granule-dependent killing

Granzymes in cancer and immunity

“…Along with granzyme A, granzyme B is one of the most abundant granzymes and, consequently, granzyme B-mediated cytotoxicity has been intensively studied. 2,24,25 Effector cells lacking granzyme B kill targets at a much slower rate than do wild-type cells, which demonstrates the important role that this protease has in executing the timely demise of infected or tumorigenic cells. 26,27 The efficiency of granzyme B-dependent killing is largely because of the ability of this protease to activate the target cell's intrinsic cell death proteases, the caspases, either directly or indirectly (Figure 2).…”

“…After a CTL/NK cell recognizes a target, cytotoxic granules move along microtubules to polarize at the plasma membrane, adjacent to the target, where they are secreted into the immunological synapse between the two cells. 2 The major constituents of cytotoxic granules are perforin and granzymes, which combine to promote rapid cell death when delivered to the target cell cytosol. The pore-forming protein, perforin, was originally thought to facilitate granzyme entry into target cells by physically forming holes in the cell membrane through which granzymes may pass.…”

“…The granule protein, perforin, promotes granzyme delivery to the target cell cytosol and, on entry, these proteases cleave their cohort of substrates to promote rapid and efficient cell death. 2 Although there are multiple granzymes, each with distinctive cell death-promoting activity, evidence implicating individual granzymes with protection from tumor formation has been relatively scarce, as mice lacking individual granzymes typically remain cancer free. Because perforin facilitates the delivery of all granzymes to target cells, CTL/NK cells from perforin-deficient mice are defective in granzyme-mediated cytotoxicity.…”

A quarter century of granzymes

“…Models proposed include the liberation of Grs from endosomal compartments of the target cells to the cytosol, or a Ca 2 þ -driven plasma membrane repair process initiated by perforin damage. 4 Grs are serine proteases, characterized by a His-Asp-Ser catalytic triad. 5 In humans, there are 5 Grs (A, B, H, K, and M) while in mice there are 10 functional Grs (A, B, C, D, E, F, G, K, M and N).…”

Improvement by death in immunity

“…10 This is followed by a comprehensive account of NK-mediated activation and recognition of target cells by Moretta et al, 11 and an overview of the detailed mechanistic aspects of CTL and NK granule-dependent killing. 12 Finally, attraction, recognition and clearance of apoptotic cells by phagocytic cells are addressed by Erwig and Henson. 13 Munro also wrote that 'a little inaccuracy sometimes saves a ton of explanation'.…”