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Molecular mechanisms of cellular mechanosensing

Abstract

Mechanical forces direct a host of cellular and tissue processes. Although much emphasis has been placed on cell-adhesion complexes as force sensors, the forces must nevertheless be transmitted through the cortical cytoskeleton. Yet how the actin cortex senses and transmits forces and how cytoskeletal proteins interact in response to the forces is poorly understood. Here, by combining molecular and mechanical experimental perturbations with theoretical multiscale modelling, we decipher cortical mechanosensing from molecular to cellular scales. We show that forces are shared between myosin II and different actin crosslinkers, with myosin having potentiating or inhibitory effects on certain crosslinkers. Different types of cell deformation elicit distinct responses, with myosin and α-actinin responding to dilation, and filamin mainly reacting to shear. Our observations show that the accumulation kinetics of each protein may be explained by its molecular mechanisms, and that protein accumulation and the cell’s viscoelastic state can explain cell contraction against mechanical load.

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Figure 1: Mechanosensitivity of myosin II in interphase Dictyostelium cells.
Figure 2: The responses of different actin-associated proteins to aspiration pressure.
Figure 3: Deformations and corresponding protein accumulation during micropipette aspiration.
Figure 4: Retraction of cells due to the accumulation of cytoskeletal proteins.

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Acknowledgements

We thank P. Devreotes, M. Iijima and their laboratory members, and members of the Robinson laboratory for reagents and discussions. We thank T. Inoue, R. Rock, R. Jensen and Robinson laboratory members for comments on the manuscript. We thank dictyBase (www.dictybase.org), D. Knecht, M. Titus, G. Gerisch, T. Egelhoff and P. Steimle for reagents. We thank V. Srivastava for help with confocal imaging. This work is supported by the National Institutes of Health grants GM066817 (to D.N.R.) and GM086704 (to D.N.R. and P.A.I.).

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T.L. and D.N.R. conceived, designed and wrote the paper. T.L. performed the experiments and analysed the data. T.L. conducted the coarse-grained molecular simulations. K.M. and P.A.I. carried out the continuum simulations. T.L., K.M., P.A.I. and D.N.R. proposed the strain-specific molecular mechanisms for different cytoskeletal proteins and the one-dimensional retraction model. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Tianzhi Luo or Douglas N. Robinson.

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The authors declare no competing financial interests.

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Luo, T., Mohan, K., Iglesias, P. et al. Molecular mechanisms of cellular mechanosensing. Nature Mater 12, 1064–1071 (2013). https://doi.org/10.1038/nmat3772

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