Cleavage of human cytosolic phospholipase A(2) by caspase-1 (ICE) and caspase-8 (FLICE)

The activation of caspases appears to play a key role in programmed cell de ath. An increasing number of substrates have been identified that are cleav ed by caspases. In a previous study, we have reported that human cPLA(2), i s proteolytically inactivated during apoptosis through cleavage by a caspas e-3-like activity. Here, we show that in cotransfection experiments the pre viously identified cleavage site at Asp(522) 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 r elated caspases-3 and -7. A different cleavage pattern of cPLA(2), was obse rved with caspase-1. Mutational analysis identified the caspase-1 cleavage site at Asp(459) within the sequence YQSD/N. Most interestingly, we found t hat even caspase-8, an upstream component of the proposed caspase cascade, cleaves cPLA(2), in vitro. The presence of multiple cleavage sites warrants proteolysis and inactivation of the proinflammatory cPLA(2) during apoptos is. (C) 1998 Academic Press.