ATG2A-mediated DAG transfer recruits DGAT2 for lipid droplet growth

Lipid droplet (LD) growth mechanisms and the roles of LD-associated lipid transfer proteins remain poorly understood. Here we show that the autophagy lipid transfer protein ATG2A has an anabolic role and promotes LD expansion by transferring diacylglycerol (DAG), triacylglycerol (TAG) and phosphatidic acid, from the endoplasmic reticulum to LDs. In ATG2A deficiency, synthesized lipids are incorporated inefficiently into LDs and assemble new LDs. In addition, DAG O-acyltransferase 2 (DGAT2), which synthesizes TAG and expands LD, fails to relocate to LDs. In vitro, DAG recruits DGAT2 to LDs. These findings support the idea that ATG2A-mediated DAG transfer recruits DGAT2 to LDs, promoting LD expansion. ATG2A alone promotes LD growth by transferring TAG and DAG, but its effectiveness in LD expansion is reduced when DGAT2 is inhibited. This synergistic action with DGAT2 prevents the buildup of nonmembrane lipids within the endoplasmic reticulum and favors TAG synthesis on the LD surface.