Decoding the impact of lipid saturation on ER signaling networks, ERSU, UPR, and ERAD

Abstract

The faithful inheritance of a functional endoplasmic reticulum (ER) in Saccharomyces cerevisiae is safeguarded by the ER Stress Surveillance (ERSU) checkpoint, which delays cytokinesis when ER homeostasis is perturbed. Under stress, ER transmission to the daughter cell is halted, while in parallel—but through independent pathways—the Unfolded Protein Response (UPR) restores ER function and ER-associated degradation (ERAD) eliminates misfolded proteins, ultimately allowing cell cycle re-entry. ER stress also transiently stimulates sphingolipid biosynthesis, with the intermediate phytosphingosine (PHS) acting as a key activator of ERSU. Yet how broader lipid parameters—such as membrane composition and saturation—reshape ER quality control and, in particular, govern ER inheritance during division remains poorly understood. To begin addressing this question, a tightly controlled experimental system was employed to selectively alter lipid saturation while monitoring ER inheritance within the context of ER homeostasis maintained by the UPR and ERAD. This analysis revealed that perturbations in lipid saturation exert specific effects on ER inheritance that are distinct from their impact on UPR activation and ERAD efficiency. These findings support a central role for lipid homeostasis in ER functional regulation and suggest that membrane lipid composition contributes to the coordination of ERSU, UPR, and ERAD during ER inheritance under stress.