Molecular motion and tridimensional nanoscale localization of kindlin control integrin activation in focal adhesions

Thomas Orré, Adrien Joly, Zeynep Karatas, Birgit Kastberger, Clément Cabriel, Ralph T. Böttcher, Sandrine Lévêque-Fort, Jean-Baptiste Sibarita, Reinhard Fässler, Bernhard Wehrle-Haller, Olivier Rossier () and Grégory Giannone ()
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Thomas Orré: University Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR
Adrien Joly: University Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR
Zeynep Karatas: University Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR
Birgit Kastberger: Department of Cell Physiology and Metabolism, Centre Médical Universitaire
Clément Cabriel: Institut des Sciences Moléculaires d’Orsay, CNRS UMR8214, Univ. Paris-Sud, Université Paris Saclay
Ralph T. Böttcher: Max Planck Institute of Biochemistry
Sandrine Lévêque-Fort: Institut des Sciences Moléculaires d’Orsay, CNRS UMR8214, Univ. Paris-Sud, Université Paris Saclay
Jean-Baptiste Sibarita: University Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR
Reinhard Fässler: Max Planck Institute of Biochemistry
Bernhard Wehrle-Haller: Department of Cell Physiology and Metabolism, Centre Médical Universitaire
Olivier Rossier: University Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR
Grégory Giannone: University Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Focal adhesions (FAs) initiate chemical and mechanical signals involved in cell polarity, migration, proliferation and differentiation. Super-resolution microscopy revealed that FAs are organized at the nanoscale into functional layers from the lower plasma membrane to the upper actin cytoskeleton. Yet, how FAs proteins are guided into specific nano-layers to promote interaction with given targets is unknown. Using single protein tracking, super-resolution microscopy and functional assays, we link the molecular behavior and 3D nanoscale localization of kindlin with its function in integrin activation inside FAs. We show that immobilization of integrins in FAs depends on interaction with kindlin. Unlike talin, kindlin displays free diffusion along the plasma membrane outside and inside FAs. We demonstrate that the kindlin Pleckstrin Homology domain promotes membrane diffusion and localization to the membrane-proximal integrin nano-layer, necessary for kindlin enrichment and function in FAs. Using kindlin-deficient cells, we show that kindlin membrane localization and diffusion are crucial for integrin activation, cell spreading and FAs formation. Thus, kindlin uses a different route than talin to reach and activate integrins, providing a possible molecular basis for their complementarity during integrin activation.

Date: 2021
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DOI: 10.1038/s41467-021-23372-w

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