Suchergebnisse

Cells remodel their structure in response to mechanical strain. However, how mechanical forces are translated into biochemical signals that coordinate the structural changes observed at the plasma membrane (PM) and the underlying cytoskeleton during mechanoadaptation is unclear. Here, we show that PM mechanoadaptation is controlled by a tension-sensing pathway composed of c-Abl tyrosine kinase and membrane curvature regulator FBP17. FBP17 is recruited to caveolae to induce the formation of caveolar rosettes. FBP17 deficient cells have reduced rosette density, lack PM tension buffering capacity under osmotic shock, and cannot adapt to mechanical strain. Mechanistically, tension is transduced to the FBP17 F-BAR domain by direct phosphorylation mediated by c-Abl, a mechanosensitive molecule. This modification inhibits FBP17 membrane bending activity and releases FBP17-controlled inhibition of mDia1-dependent stress fibers, favoring membrane adaptation to increased tension. This mechanoprotective mechanism adapts the cell to changes in mechanical tension by coupling PM and actin cytoskeleton remodeling. ; This study was supported by grants from the Spanish Ministry of Economy, Industry and Competitiveness (MINECO)/Agencia Estatal de Investigación (AEI)/European Regional Development Fund (ARDF/FEDER) "A way to make Europe" Grants (MINECO; SAF2011–25047, SAF2014–51876-R, SAF2017–83130-R, IGP-SO grant MINSEV1512–07–2016, CSD2009–0016 and BFU2016–81912-REDC), Fundació La Marató de TV3 (674/C/2013), and the Worldwide Cancer Research Foundation (♯15–0404), all to M.A.D.P. M.G.-G. is sponsored by a FPU fellowship (FPU15/03776). This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 641639. D.D.S. is supported by grants PGC2018–099321-B-I00 and RYC-2016–19590 from the Spanish Ministry of Science, Innovation and Universities. J.A.-C. acknowledges funding from MINECO grants, BIO2017–83640-P (AEI/FEDER, UE) and RYC-2014–16604. J.A.-C. and M.A.D.P. are members of the Tec4Bio consortium (ref. P2018/NMT4443; "Actividades de I+D entre Grupos de Investigación en Tecnologías," Comunidad Autónoma de Madrid/FEDER, Spain). C.H.-L. is recipient of an FPI predoctoral fellowship (BES-2015–073191). C.L. is supported by institutional grants from the Curie Institute, INSERM, and CNRS and by grants from Association Française contre les Myopathies (CAV-STRESS-MUS no. 14293), Agence Nationale de la Recherche (MOTICAV ANR-17-CE13–0020–01), the Fondation ARC pour la Recherche sur le Cancer (Programme Labellisé PGA1-RF20170205456), and programme ECOS no. C17S03. R.G.P. was supported by the National Health and Medical Research Council (NHMRC) of Australia (program grant, APP1037320 and Senior Principal Research Fellowship, 569452) and the Australian Research Council Centre of Excellence (CE140100036). We acknowledge the Australian Microscopy & Microanalysis Research Facility at the Center for Microscopy and Microanalysis at The University of Queensland. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovación y Universidades (MCNU), and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015–0505). ; Sí