The Batten disease gene product CLN5 is the lysosomal bis(monoacylglycero)phosphate synthase
2023; American Association for the Advancement of Science; Volume: 381; Issue: 6663 Linguagem: Inglês
10.1126/science.adg9288
ISSN1095-9203
AutoresUche N. Medoh, Andy Hims, Julie Y. Chen, Ali Ghoochani, Kwamina Nyame, Wentao Dong, Monther Abu-Remaileh,
Tópico(s)Calcium signaling and nucleotide metabolism
ResumoLysosomes critically rely on bis(monoacylglycero)phosphate (BMP) to stimulate lipid catabolism, cholesterol homeostasis, and lysosomal function. Alterations in BMP levels in monogenic and complex neurodegeneration suggest an essential function in human health. However, the site and mechanism responsible for BMP synthesis have been subject to debate for decades. Here, we report that the Batten disease gene product CLN5 is the elusive BMP synthase (BMPS). BMPS-deficient cells exhibited a massive accumulation of the BMP synthesis precursor lysophosphatidylglycerol (LPG), depletion of BMP species, and dysfunctional lipid metabolism. Mechanistically, we found that BMPS mediated synthesis through an energy-independent base exchange reaction between two LPG molecules with increased activity on BMP-laden vesicles. Our study elucidates BMP biosynthesis and reveals an anabolic function of late endosomes/lysosomes.
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