Compressive force from the nuclear envelope in dividing S. pombe alters binding of mitotic spindle proteins and regulates microtubule dynamics

ABSTRACT During closed mitosis in S. pombe , the nuclear envelope and mitotic spindle must work together to ensure successful nuclear division. Previous work has demonstrated that mechanical force from the nuclear envelope, transmitted through spindle pole bodies, can reshape the spindle. However, it remains unclear how force from the nuclear envelope might regulate binding or other biochemical properties of microtubule associated proteins (MAPs) in the spindle. Here, we investigate how force reprograms the spindle with two approaches: chronically increasing nuclear envelope tension via the lipid synthesis inhibitor cerulenin, and acutely applying force to the nucleus through an optical trap. Both perturbations slow spindle elongation dynamics and reduce microtubule density. Despite this reduction, key spindle proteins Ase1 and Klp5 increase their density at the spindle midzone, indicating inward force from the nuclear envelope can alter MAP binding in the spindle. We find that while motor proteins Klp5 and Klp6 only minimally affect the spindle’s response to increased nuclear envelope force, the combination of removing Ase1 and increasing nuclear envelope force together rescues spindle microtubule stability. Together, our findings reveal that nuclear force on the spindle does not merely alter its shape, but is key in regulating its biochemistry to maintain force balance and ensure cellular function. SIGNIFICANCE Accurate chromosome segregation depends on the mechanical integrity of the mitotic spindle, yet how cells sense and respond to spindle destabilization remains poorly understood. Here, we show that disrupting the force balance between the nuclear envelope and spindle in the fission yeast S. pombe activates a compensatory response that promotes microtubule formation and restores spindle elongation. Through both optical trapping and pharmacological perturbation, we identify Ase1 as a critical stabilizer of spindle mechanics and demonstrate that cells can adapt to mechanical failure through regulation of spindle protein binding. These findings uncover a mechanotransduction feedback mechanism that links spindle force balance to cytoskeletal remodeling during mitosis.