Lipid saturation induces degradation of squalene epoxidase for sterol homeostasis and cell survival

Abstract

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 geneOLE1in the budding yeastSaccharomyces cerevisiae. 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 theole1mutant, whereas the stable Erg1 causes aberrant ER and severely compromises the growth ofole1, which are recapitulated bydoa10deletion. The toxicity of the stable Erg1 anddoa10deletion is due to the accumulation of lanosterol and misfolded proteins inole1. Our study identifies Erg1 as a novel lipid saturation–regulated ERAD target, manifesting a close link between lipid homeostasis and proteostasis that maintains sterol homeostasis under the lipid saturation condition for cell survival.