ABSTRACT
Phospholipid homeostasis in biological membranes is essential to maintain cellular functions of organelles such as the endoplasmic reticulum. Phospholipid perturbation has been associated to non-alcoholic fatty liver disease, obesity and other metabolic disorders. However, in most cases, the biological significance of lipid disequilibrium remains unclear. Previously, we reported that Saccharomyces cerevisiae adapts to lipid disequilibrium by upregulating several protein quality control pathways such as the endoplasmic reticulum-associated degradation (ERAD) pathway and the unfolded protein response. Surprisingly, we observed certain ER-resident transmembrane proteins (TPs), part of the UPR programme, to be destabilised under lipid perturbation (LP). Among these, Sbh1 was prematurely degraded by dissociating from the Sec61 complex due to fatty acid remodelling and membrane stiffening of the ER. Sbh1 is targeted for degradation through its highly conserved lysine residue near the membrane in a Doa10-dependent manner. Premature removal of key ER-resident TPs might be an underlying cause of chronic ER stress in metabolic disorders.