Epithelial cells can become polyploid upon tissue injury, but mechanosensitive cues that trigger this state are poorly understood. Using an Madin Darby Canine Kidney (MDCK) cell knock-out/reconstitution system, we show that α-catenin mutants that alter force-sensitive binding to F-actin or middle (M)-domain promote cytokinesis failure and binucleation, particularly near epithelial wound-fronts. We identified Leucine Zipper Tumor Suppressor 2 (LZTS2), a factor previously implicated in abscission, as a conformation sensitive proximity partner of α-catenin. We show that LZTS2 enriches not only at midbody/intercellular bridges but also at apical adhering junctions. α-Catenin mutants with persistent M-domain opening show elevated junctional enrichment of LZTS2 compared with wild-type cells. LZTS2 knock-down leads to elevated rates of binucleation. These data implicate LZTS2 as a mechanosensitive effector of α-catenin that is critical for cytokinetic fidelity. This model rationalizes how persistent mechanoactivation of α-catenin may drive tension-induced polyploidization of epithelia after injury and suggests an underlying mechanism for how pathogenic α-catenin M-domain mutations drive macular dystrophy.
© 2025 Wang et al.