CLN6 is a glycerophosphoglycerol epimerase in bis(monoacylglycero)phosphate biosynthesis

Abstract

Lysosomal catabolism depends on bis(monoacylglycero)phosphate (BMP), a phospholipid with atypical S,S stereochemistry of unknown biosynthetic origin. CLN8 and CLN5 catalyze sequential acylation steps in BMP synthesis, and their loss of function causes Batten disease, a group of inherited neurodegenerative lysosomal storage disorders. Here we identify CLN6, a biochemically uncharacterized endoplasmic reticulum protein whose loss also causes Batten disease, as the calcium-dependent glycerophosphoglycerol epimerase that establishes BMP stereochemistry upstream of CLN8. CLN6 deficiency depletes BMP in cells, mice, and patient lysosomes, and reduces lysosomal hydrolase levels. BMP-precursor supplementation bypasses CLN6, restores BMP and increases hydrolase abundance in CLN6-deficient cells and mice. These findings place three Batten disease proteins in a single biosynthetic pathway and reveal BMP deficiency as a reversible cause of disrupted lysosomal hydrolase homeostasis.