TRAM-LAG1-CLN8 family proteins are acyltransferases regulating phospholipid composition.
Science advances 2025 ; 11: eadr3723.
DOI : 10.1126/sciadv.adr3723
PubMed ID : 39970228
PMCID : PMC11838012
URL : https://www.science.org/doi/10.1126/sciadv.adr3723
Abstract
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 (TLCD)-containing proteins are phospholipid remodeling enzymes.
We demonstrate that TLCD1 is an evolutionarily conserved lysophosphatidylethanolamine acyltransferase, which regulates cellular phospholipid composition and generates previously undescribed fatty acid and thiamine (vitamin B1) esters as its secondary products. Furthermore, we establish that human TLCD protein CLN8, mutations of 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 family of acyltransferases integral to cellular membrane phospholipid homeostasis and human disease.