Cleavage of human cytosolic phospholipase A2 by caspase-1 (ICE) and caspase-8 (FLICE).

The activation of caspases appears to play a key role in programmed cell death. An increasing number of substrates have been identified that are cleaved by caspases. In a previous study, we have reported that human cPLA2 is proteolytically inactivated during apoptosis through cleavage by a caspase-3-like activity. Here, we show that in cotransfection experiments the previously identified cleavage site at Asp522 can be used by a wide variety of caspases belonging to different subfamilies. The formation of additional fragments implied differences in cleavage site usage between the closely related caspases-3 and -7. A different cleavage pattern of cPLA2 was observed with caspase-1. Mutational analysis identified the caspase-1 cleavage site at Asp459 within the sequence YQSD/N. Most interestingly, we found that even caspase-8, an upstream component of the proposed caspase cascade, cleaves cPLA2 in vitro. The presence of multiple cleavage sites warrants proteolysis and inactivation of the proinflammatory cPLA2 during apoptosis.