Decoding the Impact of Lipid Saturation on ER Signaling Networks, ERSU, UPR, and ERAD

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, saturation, and fluidity-reshape ER quality control and, in particular, govern ER inheritance during division remains poorly understood. To address this, we employed a tightly controlled experimental system to selectively alter lipid saturation and phospholipid composition while monitoring ER inheritance within the framework of ER homeostasis maintained by UPR and ERAD. Strikingly, we found that perturbations in lipid balance exerted specific effects on ER inheritance that were distinct from their impact on UPR and ERAD. These findings reveal lipid homeostasis as a critical integrator of ER functional regulation, linking ERSU, UPR, and ERAD into a unified adaptive network that ensures robust ER transmission and cellular resilience under stress.