Elevated SUN1 promotes aging-related polarity defects through mechanical coupling microtubules to the nuclear lamina

Abstract

In migratory fibroblasts, the front-rear polarity required for cell migration is defined by an anterior centrosome relative to the nucleus. To achieve this polarity, actin cables drive the nucleus backward by coupling to nuclear membrane proteins nesprin-2G and SUN2. Aging disrupts this cell polarity by increasing the protein levels of SUN1, a SUN2 homolog. Here, we investigated the molecular mechanisms behind this disruption and found that the dominant negative effect of SUN1 and progerin, an aging-related lamin A variant, required direct SUN1-lamin A interaction. Microtubule interaction and force transmission through a nesprin, identified as nesprin-2, are crucial for SUN1s effect. We further discovered that stable microtubules are both necessary and sufficient to inhibit cell polarity. Using SUN1-SUN2 chimeric proteins, we demonstrated that the SUN domains determine their roles in cell polarization. Our findings reveal how elevated SUN1 disrupts cell polarity through coupling microtubule and nuclear lamina, emphasizing the impact of altered microtubule stability and nuclear mechanotransduction in aging.