Lysosomal phospholipase A2 (LPLA2)

Lysosomal phospholipase A2 (LPLA2), encoded by the PLA2G15 gene, is a unique member of the phospholipase A2 family characterized by its localization to lysosomes and an acidic pH optimum [1, 16]. It plays a critical role in the degradation of phospholipids, particularly within alveolar macrophages where it catabolizes pulmonary surfactant [1, 2, 16]. Beyond its hydrolase activity, LPLA2 also functions as a transacylase, transferring fatty acids to ceramide to form 1-O-acylceramide [1, 16]. Recent research has identified LPLA2 as a primary hydrolase for bis(monoacylglycero)phosphate (BMP), a lipid essential for lysosomal membrane integrity and cholesterol trafficking [7, 8, 16]. In the context of disease, LPLA2 is the primary target of cationic amphiphilic drugs (CADs) like amiodarone and fosinopril, which inhibit the enzyme and lead to drug-induced phospholipidosis (DIPL) [3, 4, 11]. Conversely, targeted inhibition of LPLA2 is being explored as a therapeutic strategy for lysosomal storage disorders such as Niemann-Pick disease type C (NPC) [5, 7, 8]. By preventing the degradation of BMP, LPLA2 inhibitors can boost BMP levels, thereby enhancing lysosomal function and ameliorating lipid accumulation and neurodegeneration [7, 8]. However, chronic inhibition or genetic deficiency of LPLA2 can lead to systemic phospholipidosis, splenomegaly, and the accumulation of surfactant in the lungs [1, 19].

Other names

PLA2G15 [1, 16]Group XV phospholipase A2 [1, 16]1-O-acylceramide synthase (ACS) [1]LYPLA3 [16]Lysosomal phospholipase A and acyltransferase [16]

Inhibition of enzymatic activity (phospholipase and transacylase) [1, 4, 11]; Inhibition of BMP hydrolysis to boost lysosomal function [7, 8].