biostudies-literatureUnknown6(1)Huang LJAcademia SinicaA fluid membrane containing a mix of unsaturated and saturated lipids is essential for life. However, it is unclear how lipid saturation might affect lipid homeostasis, membrane-associated proteins, and membrane organelles. Here, we generate temperature-sensitive mutants of the sole fatty acid desaturase gene <i>OLE1</i> in the budding yeast <i>Saccharomyces cerevisiae</i> Using these mutants, we show that lipid saturation triggers the endoplasmic reticulum-associated degradation (ERAD) of squalene epoxidase Erg1, a rate-limiting enzyme in sterol biosynthesis, via the E3 ligase Doa10-Ubc7 complex. We identify the P469L mutation that abolishes the lipid saturation-induced ERAD of Erg1. Overexpressed WT or stable Erg1 mutants all mislocalize into foci in the <i>ole1</i> mutant, whereas the sLife science alliancee202201612https://www.ebi.ac.uk/biostudies/studies/S-EPMC9652772biostudies-literatureLipid saturation induces degradation of squalene epoxidase for sterol homeostasis and cell survival.PMC9652772Huang LJChen RHfalseLipid saturation induces degradation of squalene epoxidase for sterol homeostasis and cell survival.A fluid membrane containing a mix of unsaturated and saturated lipids is essential for life. However, it is unclear how lipid saturation might affect lipid homeostasis, membrane-associated proteins, and membrane organelles. Here, we generate temperature-sensitive mutants of the sole fatty acid desaturase gene <i>OLE1</i> in the budding yeast <i>Saccharomyces cerevisiae</i> Using these mutants, we show that lipid saturation triggers the endoplasmic reticulum-associated degradation (ERAD) of squalene epoxidase Erg1, a rate-limiting enzyme in sterol biosynthesis, via the E3 ligase Doa10-Ubc7 complex. We identify the P469L mutation that abolishes the lipid saturation-induced ERAD of Erg1. Overexpressed WT or stable Erg1 mutants all mislocalize into foci in the <i>ole1</i> mutant, whereas the s2023-01-01T00:00:00Z2023 Jan2025-04-25T23:36:07.724Z2025-04-06T09:24:04.824ZS-EPMC96527723636890810.26508/lsa.202201612