PLA2 activity is required for nuclear shrinkage in caspase-independent cell death

Abstract

Apoptosis is defined on the basis of morphological changes like nuclear fragmentation and chromatin condensation, which are dependent on caspases. Many forms of caspase-independent cell death have been reported, but the mechanisms are still poorly understood. We found that hypoxic cell death was independent of caspases and was associated with significant nuclear shrinkage. Neither Bcl-2 nor Apaf-1 deficiency prevented hypoxic nuclear shrinkage. To understand the molecular mechanism of the nuclear shrinkage, we developed an in vitro system using permeabilized cells, which allowed us to purify a novel member of the phospholipase A₂ (PLA₂) family that induced nuclear shrinkage. Purified PLA₂ induced nuclear shrinkage in our permeabilized cell system. PLA₂ inhibitors prevented hypoxic nuclear shrinkage in cells and cell death. Hypoxia caused elevation of PLA₂ activity and translocation of intracellular PLA₂s to the nucleus. Knockdown of the Ca²⁺-independent PLA₂ delayed nuclear shrinkage and cell death. These results indicate that Ca²⁺-independent PLA₂ is crucial for a caspase-independent cell death signaling pathway leading to nuclear shrinkage.