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Apoptosis Initiated by Granulysin A Distinct Pathway of Cell-Mediated

Granulysin is an antimicrobial and tumoricidal molecule expressed in granules of CTL and NK cells. In this study, we show that granulysin damages cell membranes based upon negative charge, disrupts the transmembrane potential ( Dc ) in mitochondria, and causes release of cytochrome c . Granulysin-induced apoptosis is blocked in cells overexpressing Bcl-2. Despite the release of cytochrome c , procaspase 9 is not processed. Nevertheless, activation of caspase 3 is observed in granulysin-treated cells, suggesting that granulysin activates a novel pathway of CTL- and NK cell-mediated death distinct from granzyme- and death receptor-induced apoptosis. The Journal of Immunology, 2001, 167: 350–356. homology of granulysin to saposins suggests that it may exert its cytolytic function and antibacterial activity via interaction with lipids. In this study, we demonstrate that granulysin disrupts negatively charged synthetic liposomes and cell membranes. Cells expressing the antiapoptotic gene Bcl-2 are protected against granulysin-induced cell death. The interaction of granulysin with cells causes a change in mitochondrial potential ( D c ) and release of cytochrome c . Surprisingly, however, procaspase 9 is not processed to its active form, although an early caspase 3 activation is observed. Thus, granulysin is a CTL- and NK cell-speciﬁc product that activates a death pathway distinct from those induced by Fas or granzymes.