Mechanosensitive biochemical imprinting of the talin interaction with DLC1 regulates RhoA activity and cardiomyocyte remodeling
During heart disease, the cardiac extracellular matrix (ECM) undergoes a structural and mechanical transformation. Cardiomyocytes sense the mechanical properties of their environment, leading to phenotypic remodeling. A critical component of the ECM mechanosensing machinery, including the protein talin, is organized at the cardiomyocyte costamere. Our previous work indicated a different talin tension, depending on the ECM stiffness, but the effects on downstream signaling remained elusive. Here, we identify that the talin interacting proteins DLC1 (deleted in liver cancer 1), RIAM (Rap1-interacting adaptor molecule), and paxillin each preferentially bind to talin at a specific ECM stiffness, this interaction is preserved in the absence of tension, and the interaction is regulated through focal adhesion kinase signaling. Moreover, DLC1 regulates cardiomyocyte RhoA activity in a stiffness-dependent way, whereby the loss of DLC1 results in myofibrillar disarray. Together, this study demonstrates a mechanism of imprinting mechanical information into the talin interactome to fine-tune RhoA activity, with impacts on cardiac health and disease.
Authors
- Katja Gehmlich (ORCID: https://orcid.org/0000-0003-4019-1844)
- Pamela Swiatlowska (ORCID: https://orcid.org/0000-0002-3705-7495)
- James A. Levitt
- Emilie Marhuenda (ORCID: https://orcid.org/0000-0003-2357-9505)
- Aishwarya Prakash (ORCID: https://orcid.org/0009-0008-5169-4248)
- Simon P. Poland (ORCID: https://orcid.org/0000-0002-5283-327X)
- Amar J. Azad
- Simon Ameer‐Beg (ORCID: https://orcid.org/0000-0001-5227-575X)
- Darren Graham Samuel Wilson
- Ioannis Xanthis
- Megan Richter
- Pragati Pandey
- Benjamin T. Goult (ORCID: https://orcid.org/0000-0002-3438-2807)
- Elisabeth Ehler (ORCID: https://orcid.org/0000-0001-5646-5964)
- Poppy O. Smith (ORCID: https://orcid.org/0000-0002-3325-5400)
- Giuseppe Faggian (ORCID: https://orcid.org/0000-0001-5371-5761)
- Davor Pavlović (ORCID: https://orcid.org/0000-0002-3171-3551)
- Thomas Iskratsch (ORCID: https://orcid.org/0000-0002-3738-7830)
- Till Kallem
Institutions
- Centre National de la Recherche Scientifique (FR)
- University of Liverpool (GB)
- Université de Bordeaux (FR)
- Queen Mary University of London (GB)
- King's College London (GB)
- British Heart Foundation (GB)
- University of Oxford (GB)
- Azienda Ospedaliera Universitaria Integrata Verona (IT)
- King's College School (GB)
- Chimie et Biologie des Membranes et des Nanoobjects (FR)
- Institut Polytechnique de Bordeaux (FR)
- Imperial College London (GB)
- University of Birmingham (GB)
Publication Details
- Journal
- Science Advances
- Published
- 2025-09-05
- DOI
- https://doi.org/10.1126/sciadv.adt6083
- Citations
- 2
- Primary Topic
- Cellular Mechanics and Interactions
- Type
- article
- Field-Weighted Citation Impact
- 2.30