AGPAT2 Acts at the Crossroads of Lipid Biosynthesis and DRP1-Mediated Er Morphogenesis

Authors

Yoshihiro Adachi
Mauricio Torres
Allen H Hunter
Woo Jung Cho
Meixia Pan
Xianlin Han
Guangwei Du
Ling Qi
Miho Iijima
Hiromi Sesaki

Language

English

Publication Date

12-12-2025

Journal

Nature Communications

DOI

10.1038/s41467-025-66474-5

PMID

41387688

PMCID

PMC12749901

PubMedCentral® Posted Date

12-12-2025

PubMedCentral® Full Text Version

Post-print

Abstract

The morphology of the endoplasmic reticulum (ER), characterized by central sheets and peripheral tubules, is controlled by membrane-shaping proteins. However, the role of lipids in ER morphogenesis remains elusive, despite the ER being the major site for lipid synthesis. Here, by examining the role of eighteen phosphatidic acid (PA)-generating enzymes in ER morphology, we identify lysophosphatidic acid acyltransferase 2 (AGPAT2) as a critical factor in mouse and human cells. AGPAT2 produces PA in the glycerophospholipid/triacylglycerol biosynthesis pathway, and its mutations cause congenital generalized lipodystrophy. We find that AGPAT2-generated PA drives ER tubulation through gene knockout, 3D structural analysis by FIB-SEM, super-resolution microscopy, lipidomics, AlphaFold, and in vitro reconstitutions of ER tubulation and AGPAT2 activity. AGPAT2 interacts with and supplies PA to the PA-binding, dynamin-related GTPase, DRP1, which subsequently tubulates the ER in a manner independent of GTP hydrolysis and oligomerization, distinct from its function in mitochondrial division. Consistently, the reduction of PA levels by ectopic expression of a PA phosphatase, LIPIN1, transforms ER tubules into sheets. Our results reveal an unforeseen interplay between lipid biosynthesis and membrane organization in the ER.

Keywords

Endoplasmic Reticulum, Animals, Humans, Acyltransferases, Mice, Phosphatidic Acids, Dynamins, Lipids, Mice, Knockout, HEK293 Cells, Lipodystrophy, Congenital Generalized, Triglycerides, Endoplasmic reticulum, Phospholipids

Published Open-Access

yes

Recommended Citation

Adachi, Yoshihiro; Torres, Mauricio; Hunter, Allen H; et al., "AGPAT2 Acts at the Crossroads of Lipid Biosynthesis and DRP1-Mediated Er Morphogenesis" (2025). Faculty, Staff and Student Publications. 5600.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5600