PLA2G15 is a BMP hydrolase and its targeting ameliorates lysosomal disease

Kwamina Nyame, Jian Xiong, Hisham N. Alsohybe, Arthur P. H. Jong, Isabelle V. Peña, Ricardo Miguel, Thijn R. Brummelkamp, Guido Hartmann, Sebastian M. B. Nijman, Matthijs Raaben, Judith A. Simcox, Vincent A. Blomen and Monther Abu-Remaileh ()
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Kwamina Nyame: Stanford University
Jian Xiong: Stanford University
Hisham N. Alsohybe: Stanford University
Arthur P. H. Jong: Science Park 301
Isabelle V. Peña: Stanford University
Ricardo Miguel: AnaPath Services GmbH
Thijn R. Brummelkamp: Science Park 301
Guido Hartmann: Science Park 301
Sebastian M. B. Nijman: Science Park 301
Matthijs Raaben: Science Park 301
Judith A. Simcox: University of Wisconsin–Madison
Vincent A. Blomen: Science Park 301
Monther Abu-Remaileh: Stanford University

Nature, 2025, vol. 642, issue 8067, 474-483

Abstract: Abstract Lysosomes catabolize lipids and other biological molecules, maintaining cellular and organismal homeostasis. Bis(monoacylglycero)phosphate (BMP), a major lipid constituent of intralysosomal vesicles, stimulates lipid-degrading enzymes and is altered in various human conditions, including neurodegenerative diseases1,2. Although lysosomal BMP synthase was recently discovered3, the enzymes mediating BMP turnover remain elusive. Here we show that lysosomal phospholipase PLA2G15 is a physiological BMP hydrolase. We further demonstrate that the resistance of BMP to lysosomal hydrolysis arises from its unique sn2, sn2′ esterification position and stereochemistry, as neither feature alone confers resistance. Purified PLA2G15 catabolizes most BMP species derived from cell and tissue lysosomes. Furthermore, PLA2G15 efficiently hydrolyses synthesized BMP stereoisomers with primary esters, challenging the long-held thought that BMP stereochemistry alone ensures resistance to acid phospholipases. Conversely, BMP with secondary esters and S,S stereoconfiguration is stable in vitro and requires acyl migration for hydrolysis in lysosomes. Consistent with our biochemical data, PLA2G15-deficient cells and tissues accumulate several BMP species, a phenotype reversible by supplementing wild-type PLA2G15 but not its inactive mutant. Targeting PLA2G15 reduces the cholesterol accumulation in fibroblasts of patients with Niemann–Pick disease type C1 and significantly ameliorates disease pathologies in Niemann–Pick disease type C1-deficient mice, leading to an extended lifespan. Our findings established the rules governing BMP stability in lysosomes and identified PLA2G15 as a lysosomal BMP hydrolase and a potential target for therapeutic intervention in neurodegenerative diseases.

Date: 2025
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DOI: 10.1038/s41586-025-08942-y

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