Is iPLA2β a Novel Target for the Development of New Strategies to Alleviate Inflammatory Bowel Disease?

Phospholipases A2 (PLA2s), lipolytic enzymes that release fatty acids (FAs) and lysophospholipids from the hydrolysis of the sn-2 ester bond of membrane glycerophospholipids, modulate (phospho)lipid-related homeostatic and stimulus-induced intracellular processes, linking lipid metabolism with cell signaling [1, 2]. Although the diverse products released by their activity on cell membranes have signaling and metabolic activities in and of themselves, the products may be further converted into hundreds of lipid mediator molecules, including arachidonic acid (AA)derived eicosanoids and x-3 polyunsaturated FA-derived pro-resolving mediators [3]. Unsurprisingly, PLA2s are involved in diverse and fundamental biological processes, including inflammation, immunity, reproduction, atherosclerosis, cancer, and neurodegeneration [2]. Among the human PLA2s, eleven members belong to the secreted PLA2 (sPLA2) family of low-molecular-mass Ca -dependent enzymes that function in the extracellular space on cell membranes, lipoproteins, bacteria, microparticles, and viruses [3, 4]. Most PLA2s are, however, intracellular enzymes, including the Ca-dependent cytosolic PLA2s (cPLA2s or group IV PLA2s) and the Ca -independent PLA2s (iPLA2s or group VI PLA2s). Among the nine enzymes within the iPLA2 family, also named the patatinlike phospholipase domain-containing lipase (PNPLA) family, iPLA2b (also PNPLA9 or group VIA PLA2) is far and away the most studied enzyme [5]. The human iPLA2b gene (PLA2G6) may undergo several alternative splicing events that generate isoforms with varying enzymatic activity and function [6]. The ‘‘classic’’ isoform of iPLA2b (group VIA-1 PLA2) is an 85-kDa enzyme with a Ser-Asp catalytic dyad, a conserved glycine-rich, nucleotide-binding motif (GXGXXG) and eight N-terminal ankyrin repeats [5]. The cellular activity of iPLA2b is regulated by ATP binding, oligomerization, binding to calmodulin, caspase-3-mediated proteolytic cleavage, and alternative splicing [5, 6]. In contrast to cPLA2, iPLA2b is not specific for AA, hydrolyzing phospholipids with no preference for their FA substituents or head groups. The biological activity of iPLA2b has been traditionally described as homeostatic membrane remodeling, which includes deacylation/reacylation cycles important for AA incorporation into phospholipids, for phosphatidylcholine (PC) turnover and cell growth, but also for excision-repair mechanisms that maintain mitochondrial membrane integrity [5]. However, recent studies have revealed a number of cell signaling-based roles for the enzyme, such as the regulation of endoplasmic reticulum (ER) stress, apoptosis, cell proliferation, differentiation, and immune cell function [5]. Analyses of mutant mouse models and clinical phenotypes have provided important insights into its (patho)physiological effects, which include osteoblastic differentiation, male fertility, b-cell function, cancer, and neurodegeneration [5]. In this issue of Digestive Diseases and Sciences, Jiao et al. [7] report a novel function for iPLA2b in the maintenance of intestinal homeostasis. The authors reported that iPLA2b deficiency significantly exacerbates pathological features in an experimental mouse model of dextran & Toni Petan toni.petan@ijs.si