Lipid-Mediated Control of ER Function During Apoptosis

Lipid metabolites can function as potent stress signals that disrupt cellular homeostasis and promote apoptosis. Here, we investigate the molecular mechanisms of endoplasmic reticulum (ER)-associated apoptosis induced by the sphingolipid-derived fatty aldehyde trans-2-hexadecenal (t-2-hex) in Saccharomyces cerevisiae. We show that t-2-hex triggers ER stress and activates the unfolded protein response (UPR) through the canonical Ire1-Hac1 pathway. We identify the short-chain dehydrogenase/reductase family member Fmp52 as a novel and essential factor required for t-2-hex detoxification at the ER. Loss of Fmp52 function sensitizes cells to lipid-induced stress, enhances UPR signaling, and disrupts proteostasis, including mitochondrial precursor protein import and the maturation of endogenous ER client proteins. Fmp52 acts synergistically with the mitochondrial aldehyde dehydrogenase Hfd1 to promote cellular tolerance to t-2-hex. Mechanistically, t-2-hex directly lipidates Kar2/BiP at a conserved cysteine residue, thereby impairing protein maturation in the ER. Notably, the human protein Tip30 functionally complements yeast Fmp52, highlighting an evolutionarily conserved protective role. Together, our findings reveal a lipid-mediated mechanism that links sphingolipid catabolism to ER proteostasis and apoptosis, and establish Fmp52/Tip30 as a previously unrecognized ER safeguard against lipid-induced cytotoxicity.