α-Catenin force-sensitive binding and sequestration of LZTS2 leads to cytokinesis failure

doi:10.1083/jcb.202308124

α-Catenin force-sensitive binding and sequestration of LZTS2 leads to cytokinesis failure

2025-01-09

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DOI：10.1083/jcb.202308124

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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 alpha-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 alpha-catenin. We show that LZTS2 enriches not only at midbody/intercellular bridges but also at apical adhering junctions. alpha-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 alpha-catenin that is critical for cytokinetic fidelity. This model rationalizes how persistent mechanoactivation of alpha-catenin may drive tension-induced polyploidization of epithelia after injury and suggests an underlying mechanism for how pathogenic alpha-catenin M-domain mutations drive macular dystrophy.

Keywords:

CELL-CELL CONTACT

E-CADHERIN

TUMOR-SUPPRESSOR

MECHANICAL STABILITY

CONTRACTILE RING

MYOSIN-II

VINCULIN

TENSION

JUNCTIONS

RHOA

α-Catenin force-sensitive binding and sequestration of LZTS2 leads to cytokinesis failure

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