Cytotoxins are a group of molecules contained within intracellular cytotoxic granules that can damage any cell membrane close to their site of release . Cytotoxins include specific proteases - granzymes, and the pore forming protein perforin [64, 65]. Granzyme B is a 32 kDa serine protease that enters the target cell by endocyto-sis, either by binding the mannose-6-phosphate receptor , or by constitutive fluid phase uptake. Once released inside the target cell from the endocytic vescicle, Granzyme B activates several pathways that altogether lead to apoptosis. Among the molecules involved is the pro-apoptotic Bid, a member of the Bcl-2 family that triggers mitochondrial outer membrane permeabilization and release of cytochrome C. In turn, caspase 9 and then caspase 3 are then activated . Damage to mito-chondrial outer membrane is the critical point in the apoptosis pathway, since, following this event, cells are committed to die .
Perforin is the single most critical component of target cell killing. Although pore formation may directly cause cell death, it may also create ports of entry for other granule components that will synergistically induce apoptosis . Sublytic perforin levels are necessary for Granzyme B to break the endosomal vesicle in which it is pinocytosed, be released into the target cell and exert its effect .
Granzymes A, C, K, and M are other proteolytic granule components that induce cell death independently of Granzyme B, but in synergy with perforin. Other components of the lytic granules, including Granzyme H and Granulysin, have been characterized, but the mechanisms by which they mediate cell death have not been elucidated.
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