Mammalian Cells Integrate Endoplasmic Reticulum and Nuclear Envelope signals to time mitotic entry

Abstract

Accurate cell division requires coordination between organelle organization and cell-cycle progression, but how architectural and functional cues from the endoplasmic reticulum (ER) and nuclear envelope (NE)--a continuous membrane network--interface with mitotic control remains unclear. Here, we demonstrate that mammalian cells integrate ER/NE structure and functions to regulate the onset and progression of mitosis. Perturbing ER function with diverse stressors causes a selective delay at the metaphase-anaphase transition, accompanied by defective spindle assembly, chromosome misalignment, and loss of coordinated ER-chromosome organization. Under these conditions, the checkpoint protein MAD1 fails to efficiently dissociate from the NE. ER stress also disrupts microtubule-organizing centers and the centriculum, an ER-derived compartment surrounding centrosomes. Restoring ER structure by expressing the shaping proteins CLIMP63(1-192) or REEP4 rescues spindle organization and mitotic progression. Conversely, transient metaphase arrest induced by partial APC/C inhibition remodels ER morphology independently of stress, and this remodeling is reversed by CLIMP63(1-192). These findings uncover a bidirectional link between ER structure function and the spindle assembly checkpoint, identifying the organelle architecture as an instructive signal that modulates mitotic timing in mammalian cell.