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 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 stable Erg1 causes aberrant ER and severely compromises the growth of <i>ole1</i>, which are recapitulated by <i>doa10</i> deletion. The toxicity of the stable Erg1 and <i>doa10</i> deletion is due to the accumulation of lanosterol and misfolded proteins in <i>ole1</i> 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.