Mechanosensitive biochemical imprinting of the talin interaction with DLC1 regulates RhoA activity and cardiomyocyte remodeling
Year: 2025
Type: article
Abstract: 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.
Source: Science Advances
Authors: Emilie Marhuenda, Ioannis Xanthis, Poppy O. Smith, Aishwarya Prakash, Till Kallem, Pragati Pandey, Darren Graham Samuel Wilson, Amar Azad, Megan Richter, Davor Pavlovic, Katja Gehmlich, Giuseppe Faggian, Pamela Swiatlowska, Elisabeth Ehler, James Levitt, Simon P. Poland, Simon Ameer-Beg, Benjamin T Goult, Thomas Iskratsch
Institutions: Centre National de la Recherche Scientifique, Université de Bordeaux, Queen Mary University of London, Chimie et Biologie des Membranes et des Nanoobjects, Institut Polytechnique de Bordeaux, University of Liverpool, University of Birmingham, University of Oxford, Imperial College London, King's College London
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,500
Awards: ISOFLIM: Isotropic resolution fluorescence lifetime imaging of 3D neuron cultures, Talin dependent mechanical imprinting as driver for cardiac disease progression, MICA: Interfering with pathological signalling in dilated cardiomyopathy, G4631287935, Accelerator Award, G7154628268, The role of ALPK3 in autosomal dominant hypertrophic cardiomyopathy. ,, The regulation of mechanosensing in healthy and atherosclerotic vascular smooth muscle cells, Investigating the cardiomyocyte rigidity sensing mechanism with micro patterned surfaces and nanopillars
OpenAlex ID: W4414011018