PR002115 (Project)

Description:The diversity of cellular phospholipids, crucial for membrane homeostasis and function, arises from enzymatic remodeling of their fatty acyl chains. In this work, we reveal that poorly understood TRAM–LAG1–CLN8 domain-containing (TLCD) proteins are phospholipid remodeling enzymes. We demonstrate that TLCD1 is an evolutionarily conserved lysophosphatidylethanolamine acyltransferase, which regulates cellular phospholipid composition and generates novel fatty acid and thiamine (vitamin B1) esters as its secondary products. Furthermore, we establish that human TLCD protein CLN8, mutations in which cause fatal neurodegenerative Batten disease, is a lysophosphatidylglycerol acyltransferase. We show that CLN8 catalyzes the essential step in the biosynthesis of bis(monoacylglycero)phosphate, a phospholipid critical for lysosome function. Our study unveils a new family of acyltransferases integral to cellular membrane phospholipid homeostasis and human disease.