Acid phospholipase A1 promotes lysosomal membrane catabolism
Tischitz, M.; Breithofer, J.; Bulfon, D.; Zitta, C.; Sahrawat, A. S.; Wagner, C.; Fawzy, N.; Züllig, T.; Oberer, M.; Hartig, L.; Pirchheim, A.; Schooltink, L.; Taschler, U.; Gruber, K.; Lass, A.; Stelzl, U.; Kolb, D.; Kratky, D.; Zimmermann, R.
Show abstract
The molecular mechanisms of lysosomal glycerophospholipid (GPL) catabolism are incompletely understood. Here, we report that acid phospholipase A1 (APLA1), formerly known as palmitoyl-protein thioesterase 2 (PPT2), is required for efficient GPL degradation. Deletion of APLA1 in human cells results in excess accumulation of phospholipids within lysosomes # a pathological condition termed phospholipidosis. APLA1 activity depends on interactions with negatively charged GPLs and is inhibited by phospholipidosis-inducing cationic amphiphilic drugs. Hydrolysis of zwitterionic, but not anionic, GPLs requires co-activation of APLA1 by the lysosome-specific lipid bis(monoacylglycero)phosphate. Upon pharmacological mTORC inhibition, which increases lysosomal GPL turnover, APLA1-deficient cells exhibit massive accumulation of multilamellar membranes in lysosomes and reduced cytosolic triacylglycerol stores. APLA1 acts in concert with lysosomal phospholipase A2 (PLA2G15). Combined APLA1/PLA2G15-deficiency leads to a severe reduction in acid phospholipase A1/A2 activity, thereby exacerbating phospholipidosis. Our observations provide detailed mechanistic insights into lysosomal GPL catabolism, a crucial pathway for maintaining lipid homeostasis.
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