CLN6 is a glycerophosphoglycerol epimerase in bis(monoacylglycero)phosphate biosynthesis
Sheokand, P. K.; James, A. M.; Posern, C.; Singh Sahrawat, A.; Breithofer, J.; Ganellin, J.; Proulx, M. K.; Leese, S. K.; Turner, K.; Lacabanne, D.; Bulfon, D.; Jenkins, B.; van der Kleij, J.; Johnston, H. E.; Lord, S. O.; Basran, M. K.; Yu, C. S.; Booth, C. D.; Weimer, J. M.; Koulman, A.; Jäättelä, M.; Kunji, E. R. S.; Palmer, D. N.; Mitchell, N. L.; Prudent, J.; Zimmermann, R.; Gruber, K.; Schulz, A.; Murphy, M. P.; Petkevicius, K.
Show 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.
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