The phospholipase A₂ superfamily as a central hub of bioactive lipids and beyond

In essence, "phospholipase A₂" (PLA₂) means a group of enzymes that release fatty acids and lysophospholipids by hydrolyzing the sn-2 position of glycerophospholipids. To date, more than 50 enzymes possessing PLA₂ or related lipid-metabolizing activities have been identified in mammals, and these are subdivided into several families in terms of their structures, catalytic mechanisms, tissue/cellular localizations, and evolutionary relationships. From a general viewpoint, the PLA₂ superfamily has mainly been implicated in signal transduction, driving the production of a wide variety of bioactive lipid mediators. However, a growing body of evidence indicates that PLA₂s also contribute to phospholipid remodeling or recycling for membrane homeostasis, fatty acid β-oxidation for energy production, and barrier lipid formation on the body surface. Accordingly, PLA₂ enzymes are considered one of the key regulators of a broad range of lipid metabolism, and perturbation of specific PLA₂-driven lipid pathways often disrupts tissue and cellular homeostasis and may be associated with a variety of diseases. This review covers current understanding of the physiological functions of the PLA₂ superfamily, focusing particularly on the two major intracellular PLA₂ families (Ca²⁺-dependent cytosolic PLA₂s and Ca²⁺-independent patatin-like PLA₂s) as well as other PLA₂ families, based on studies using gene-manipulated mice and human diseases in combination with comprehensive lipidomics.