Distinct roles of two intracellular phospholipase A(2)s in fatty acid release in the cell death pathway - Proteolytic fragment of type IVA cytosolic phospholipase A(2)alpha inhibits stimulus-induced arachidonate release, whereas that of type VICa2+-independent phospholipase A(2) augments spontaneous fatty acid release

Cytosolic phospholipase A(2)alpha (cPLA(2)alpha; type IVA), an essential in itiator of stimulus-dependent arachidonic acid (AA) metabolism, underwent c aspase-mediated cleavage at Asp(522) during apoptosis. Although the resulta nt catalytically inactive N-terminal fragment, cPLA(2)(1-522), was inessent ial for cell growth and the apoptotic process, it was constitutively associ ated with cellular membranes and attenuated both the A23187-elicited immedi ate and the interleukin-1-dependent delayed phases of AA release by several phospholipase A(2)s (PLA(2)s) involved in eicosanoid generation, without a ffecting spontaneous AA release by PLA(2)s implicated in phospholipid remod eling. Confocal microscopic analysis revealed that cPLA(2)(1-522) was distr ibuted in the nucleus. Pharmacological and transfection studies revealed th at Ca2+-independent PLA(2) (iPLA(2); type VI), a phospholipid remodeling PL A(2), contributes to the cell death-associated increase in fatty acid relea se. iPLA(2) was cleaved at Asp(183) by caspase-3 to a truncated enzyme lack ing most of the first ankyrin repeat, and this cleavage resulted in increas ed iPLA(2) functions, iPLA(2) had a significant influence on cell growth or death, according to cell type. Collectively, the caspase-truncated form of cPLA(2)alpha behaves like a naturally occurring dominant-negative molecule for stimulus-induced AA release, rendering apoptotic: cells no longer able to produce lipid mediators, whereas the caspase-truncated form of iPLA(2) accelerates phospholipid turnover that may lead to apoptotic membranous cha nges.