Calcium-independent phospholipases A2 and their roles in biological processes and diseases

Abstract

Among the family of phospholipases A2 (PLA2s) are the Ca(2+)-independent PLA2s (iPLA2s) and they are designated group VI iPLA2s. In relation to secretory and cytosolic PLA2s, the iPLA2s are more recently described and details of their expression and roles in biological functions are rapidly emerging. The iPLA2s or patatin-like phospholipases (PNPLAs) are intracellular enzymes that do not require Ca(2+) for activity, and contain lipase (GXSXG) and nucleotide-binding (GXGXXG) consensus sequences. Though nine PNPLAs have been recognized, PNPLA8 (membrane-associated iPLA2γ) and PNPLA9 (cytosol-associated iPLA2β) are the most widely studied and understood. The iPLA2s manifest a variety of activities in addition to phospholipase, are ubiquitously expressed, and participate in a multitude of biological processes, including fat catabolism, cell differentiation, maintenance of mitochondrial integrity, phospholipid remodeling, cell proliferation, signal transduction, and cell death. As might be expected, increased or decreased expression of iPLA2s can have profound effects on the metabolic state, CNS function, cardiovascular performance, and cell survival; therefore, dysregulation of iPLA2s can be a critical factor in the development of many diseases. This review is aimed at providing a general framework of the current understanding of the iPLA2s and discussion of the potential mechanisms of action of the iPLA2s and related involved lipid mediators.

Keywords: alternate splicing; arachidonic acid; cancers; central nervous system disorders; docosahexaenoic acid; eicosanoids; immune responses; inflammation; membrane homeostasis; signaling; β-cells.

Fig. 1.

Proposed roles for iPLA₂β-derived lipid signals in promoting β-cell death leading to T1D. Our collection of studies reveal that iPLA₂β activation is associated with processes that lead to β-cell apoptosis. The bioactive lipids (and their metabolites), derived from iPLA₂β-catalyzed hydrolysis of membrane phospholipids, are proposed to trigger: a) generation of pro-apoptotic sphingolipids, pro-apoptotic variants of apoptotic factors, and autophagy dysfunction to promote β-cell death; and b) inflammatory responses, immune cell functionality, and chemotaxis to promote immune responses, which serve to amplify the β-cell death process. We suggest that these effects of iPLA₂β-derived lipids, working in concert, contribute to the onset and progression of β-cell death, which eventually leads to the development of T1D.

Fig. 2.

Biological roles and consequences of iPLA₂ activation. The different isoforms of iPLA₂ (δ, ε, ζ, η, γ, and β) manifest cell/organelle-specific roles by expressing a variety of activities at the plasma membrane, ER, mitochondria, peroxisomes, and nucleus. The outcomes can be homeostatic and beneficial under normal conditions, but when the expression and/or activity are dysregulated (increased or decreased), they can be detrimental and lead to a variety of disorders. While the illustration describes the involvement of iPLA₂s, it might be expected that cPLA₂s and sPLA₂s, in a cell/organelle-specific manner, participate in a sequential manner or in concert with the iPLA₂s to produce the various outcomes.