A regulator of amino acid sensing links lipid peroxidation and lipid droplet-dependent antioxidant response

Recent studies highlight the antioxidant role of lipid droplets (LDs) in shielding unsaturated lipids from peroxidation. While LDs accumulate during oxidative stress, the underlying mechanism remains unclear. Our previous research revealed that intracellular amino acids directly bind to and activate the E3 ubiquitin ligase Ubr1 to degrade Plin2, an LD protein inhibiting lipolysis. Here, we unexpectedly find that Ubr1's ability to bind to amino acids is inhibited during oxidative stress. Mechanistically, oxidative stress-induced lipid peroxidation blocks the activity of Hsc70-4, an ATPase that maintains the amino-acid-binding ability of Ubr1. 4-hydroxynonenal, a reactive product of lipid peroxidation, covalently modifies and inactivates Hsc70-4, leading to Ubr1 inactivation, Plin2 stabilization, and LD accumulation. Increased LDs minimize lipid peroxidation, thus protecting cells from oxidative damage and cell death. Together, we identify a regulator of amino acid sensing with redox-dependent activity, bridging the gap in understanding how lipid peroxidation stimulates LD-dependent antioxidant responses.