Cellular mechanism linking endoplasmic reticulum inheritance and cell cycle regulation of the nuclear genome

Endoplasmic reticulum (ER) stress triggers activation of the ER surveillance (ERSU) pathway— a critical protective mechanism that transiently halts cortical ER inheritance to daughter cells and arrests cytokinesis by septin ring subunit Shs1 re-localization to the bud scar in response to ER stress. Once ER functional homeostasis is re-established, cells resume normal cell cycle progression; however, the molecular circuitry linking ER integrity to cell cycle regulation has remained largely unresolved. Here, we show that ER stress selectively disperse Bud2, a GAP for Bud1/Rsr1, severing its canonical role in cell polarity while integrating it into ER homeostasis signaling. Bud2 dispersion results in accelerated spindle pole body (SPB) duplication, spindle misorientation, defects in nuclear migration, and genome segregation errors under ER stress. Strikingly, a C-terminal truncation of Shs1 ( shs1-ΔCTD ) recapitulated the ER stress–induced dispersion of Bud2 phenotype even in the absence of ER stress, and delayed cell-cycle re-entry after ER homeostasis was regained—despite normal occurrence of typical ERSU hallmark events. Notably, Bud2 overexpression rescued the growth defects of shs1-ΔCTD mutants after ER homeostasis was re-established. Collectively, our findings reveal a new mechanistic axis whereby ER integrity coordinates organelle inheritance, cytoskeletal organization, and nuclear division via selective control of Bud2 and Shs1, establishing a direct regulatory bridge between ER status and mitotic fidelity.