Lipidomics analysis of WT and CLN5-deficient HEK293T cells, iPSCs, and iNeurons

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 exhibit a
massive accumulation of the BMP synthesis precursor
lysophosphatidylglycerol (LPG), depletion of BMP species, and
dysfunctional lipid metabolism. Mechanistically, we demonstrate that BMPS
mediates synthesis through an energy-independent base exchange reaction
between two LPG molecules with increased activity on BMP-laden vesicles.
Our study resolves the long-sought BMP biosynthetic route and reveals a
novel anabolic function of late endosomes/lysosomes.