The Batten disease gene product CLN5 is the lysosomal bis(monoacylglycero)phosphate synthase

• 成果类型: Article
• 署名作者: Medoh, Uche N.; Hims, Andy; Chen, Julie Y.; Ghoochani, Ali; Nyame, Kwamina; Dong, Wentao; Abu-Remaileh, Monther
• 署名单位: Stanford University; Stanford University; Stanford University; Stanford University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-10041
• DOI: 10.1126/science.adg9288
• 发表日期: 2023-09-15
• 页码: 1182-1188
• 关键词: drug-induced phospholipidosis; late endosome; biosynthesis; lipids; bis(monoacylglycerol)phosphate; transacylase; metabolism

摘要

Lysosomes 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.