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.
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January 09 2025
α-Catenin force-sensitive binding and sequestration of LZTS2 leads to cytokinesis failure
Yuou Wang
,
Yuou Wang
*
(Data curation, Formal analysis, Investigation, Methodology, Software, Validation, Visualization, Writing - original draft, Writing - review & editing)
1Department of Pulmonary Medicine,
Northwestern University Feinberg School of Medicine
, Chicago, IL, USA
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Alex Yemelyanov
,
Alex Yemelyanov
*
(Investigation, Methodology)
1Department of Pulmonary Medicine,
Northwestern University Feinberg School of Medicine
, Chicago, IL, USA
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Christopher D. Go
,
Christopher D. Go
(Investigation, Resources)
2
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health
, Toronto, Canada
3Department of Molecular Genetics,
University of Toronto
, Toronto, Canada
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Sun K. Kim
,
Sun K. Kim
(Formal analysis, Investigation)
5Department of Cell and Developmental Biology,
Northwestern University Feinberg School of Medicine
, Chicago, IL, USA
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Jeanne M. Quinn
,
Jeanne M. Quinn
(Formal analysis, Investigation, Methodology, Validation)
1Department of Pulmonary Medicine,
Northwestern University Feinberg School of Medicine
, Chicago, IL, USA
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Annette S. Flozak
,
Annette S. Flozak
(Data curation, Formal analysis, Investigation, Resources, Validation, Visualization, Writing - review & editing)
1Department of Pulmonary Medicine,
Northwestern University Feinberg School of Medicine
, Chicago, IL, USA
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Phuong M. Le
,
Phuong M. Le
(Visualization)
1Department of Pulmonary Medicine,
Northwestern University Feinberg School of Medicine
, Chicago, IL, USA
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Shannon Liang
,
Shannon Liang
(Formal analysis, Visualization)
1Department of Pulmonary Medicine,
Northwestern University Feinberg School of Medicine
, Chicago, IL, USA
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Anne-Claude Gingras
,
Anne-Claude Gingras
(Data curation, Investigation, Supervision, Writing - review & editing)
2
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health
, Toronto, Canada
3Department of Molecular Genetics,
University of Toronto
, Toronto, Canada
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Mitsu Ikura
,
Mitsu Ikura
(Resources)
4Department of Medical Biophysics,
University Health Network, Princess Margaret Cancer Center, University of Toronto
, Toronto, Canada
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Noboru Ishiyama
,
Noboru Ishiyama
(Investigation, Methodology)
4Department of Medical Biophysics,
University Health Network, Princess Margaret Cancer Center, University of Toronto
, Toronto, Canada
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Cara J. Gottardi
(Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing)
1Department of Pulmonary Medicine,
Northwestern University Feinberg School of Medicine
, Chicago, IL, USA
5Department of Cell and Developmental Biology,
Northwestern University Feinberg School of Medicine
, Chicago, IL, USA
Correspondence to Cara J. Gottardi: [email protected]
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Yuou Wang
Data curation, Formal analysis, Investigation, Methodology, Software, Validation, Visualization, Writing - original draft, Writing - review & editing
*
1Department of Pulmonary Medicine,
Northwestern University Feinberg School of Medicine
, Chicago, IL, USA
1Department of Pulmonary Medicine,
Northwestern University Feinberg School of Medicine
, Chicago, IL, USA
Christopher D. Go
Investigation, Resources
2
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health
, Toronto, Canada
3Department of Molecular Genetics,
University of Toronto
, Toronto, Canada
Sun K. Kim
Formal analysis, Investigation
5Department of Cell and Developmental Biology,
Northwestern University Feinberg School of Medicine
, Chicago, IL, USA
Jeanne M. Quinn
Formal analysis, Investigation, Methodology, Validation
1Department of Pulmonary Medicine,
Northwestern University Feinberg School of Medicine
, Chicago, IL, USA
Annette S. Flozak
Data curation, Formal analysis, Investigation, Resources, Validation, Visualization, Writing - review & editing
1Department of Pulmonary Medicine,
Northwestern University Feinberg School of Medicine
, Chicago, IL, USA
Phuong M. Le
Visualization
1Department of Pulmonary Medicine,
Northwestern University Feinberg School of Medicine
, Chicago, IL, USA
Shannon Liang
Formal analysis, Visualization
1Department of Pulmonary Medicine,
Northwestern University Feinberg School of Medicine
, Chicago, IL, USA
Anne-Claude Gingras
Data curation, Investigation, Supervision, Writing - review & editing
2
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health
, Toronto, Canada
3Department of Molecular Genetics,
University of Toronto
, Toronto, Canada
Mitsu Ikura
Resources
4Department of Medical Biophysics,
University Health Network, Princess Margaret Cancer Center, University of Toronto
, Toronto, Canada
Noboru Ishiyama
Investigation, Methodology
4Department of Medical Biophysics,
University Health Network, Princess Margaret Cancer Center, University of Toronto
, Toronto, Canada
Cara J. Gottardi
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1Department of Pulmonary Medicine,
Northwestern University Feinberg School of Medicine
, Chicago, IL, USA
5Department of Cell and Developmental Biology,
Northwestern University Feinberg School of Medicine
, Chicago, IL, USA
Correspondence to Cara J. Gottardi: [email protected]
*
Y. Wang and A. Yemelyanov share co-first authorship.
Disclosures: The authors declare no competing interests exist.
Received:
August 29 2023
Revision Received:
October 11 2024
Accepted:
December 09 2024
Online ISSN: 1540-8140
Print ISSN: 0021-9525
Funder(s):
Terry Fox Research Institute
- Award Id(s): TFRI PPG 1107
Funder(s):
National Institutes of Health
- Award Id(s): HL163611,GM129312,F30EY036267
© 2025 Wang et al.
2024
Wang et al.
This article is distributed under the terms as described at https://rupress.org/pages/terms102024/.
J Cell Biol (2025) 224 (3): e202308124.
Article history
Received:
August 29 2023
Revision Received:
October 11 2024
Accepted:
December 09 2024
Citation
Yuou Wang, Alex Yemelyanov, Christopher D. Go, Sun K. Kim, Jeanne M. Quinn, Annette S. Flozak, Phuong M. Le, Shannon Liang, Anne-Claude Gingras, Mitsu Ikura, Noboru Ishiyama, Cara J. Gottardi; α-Catenin force-sensitive binding and sequestration of LZTS2 leads to cytokinesis failure. J Cell Biol 3 March 2025; 224 (3): e202308124. doi: https://doi.org/10.1083/jcb.202308124
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