The plasma membrane as a mechanochemical transducer

Cells are constantly submitted to external mechanical stresses, which they must withstand and respond to. By forming a physical boundary between cells and their environment that is also a biochemical platform, the plasma membrane (PM) is a key interface mediating both cellular response to mechanical stimuli, and subsequent biochemical responses. Here, we review the role of the PM as a mechanosensing structure. We first analyse how the PM responds to mechanical stresses, and then discuss how this mechanical response triggers downstream biochemical responses. The molecular players involved in PM mechanochemical transduction include sensors of membrane unfolding, membrane tension, membrane curvature or membrane domain rearrangement. These sensors trigger signalling cascades fundamental both in healthy scenarios and in diseases such as cancer, which cells harness to maintain integrity, keep or restore homeostasis and adapt to their external environment. This article is part of a discussion meeting issue ‘Forces in cancer: interdisciplinary approaches in tumour mechanobiology’.

High-intensity focused ultrasound-induced mechanochemical transduction in synthetic elastomers

While study in the field of polymer mechanochemistry has yielded mechanophores that perform various chemical reactions in response to mechanical stimuli, there is not yet a triggering method compatible with biological systems. Applications such as using mechanoluminescence to generate localized photon flux in vivo for optogenetics would greatly benefit from such an approach. Here we introduce a method of triggering mechanophores by using high-intensity focused ultrasound (HIFU) as a remote energy source to drive the spatially and temporally resolved mechanical-to-chemical transduction of mechanoresponsive polymers. A HIFU setup capable of controlling the excitation pressure, spatial location, and duration of exposure is employed to activate mechanochemical reactions in a cross-linked elastomeric polymer in a noninvasive fashion. One reaction is the chromogenic isomerization of a naphthopyran mechanophore embedded in a polydimethylsiloxane (PDMS) network. Under HIFU irradiation evidence of the mechanochemical transduction is the observation of a reversible color change as expected for the isomerization. The elastomer exhibits this distinguishable color change at the focal spot, depending on ultrasonic exposure conditions. A second reaction is the demonstration that HIFU irradiation successfully triggers a luminescent dioxetane, resulting in localized generation of visible blue light at the focal spot. In contrast to conventional stimuli such as UV light, heat, and uniaxial compression/tension testing, HIFU irradiation provides spatiotemporal control of the mechanochemical activation through targeted but noninvasive ultrasonic energy deposition. Targeted, remote light generation is potentially useful in biomedical applications such as optogenetics where a light source is used to trigger a cellular response.

Rapid flow-induced activation of Gαq/11 is independent of Piezo1 activation

Endothelial cell (EC) mechanochemical transduction is the process by which mechanical stimuli are sensed by ECs and transduced into biochemical signals and ultimately into physiological responses. Identifying the mechanosensor/mechanochemical transducer(s) and describing the mechanism(s) by which they receive and transmit the signals has remained a central focus within the field. The heterotrimeric G protein, Gαq/11, is proposed to be part of a macromolecular complex together with PECAM-1 at EC junctions and may constitute the mechanochemical transducer as it is rapidly activated within seconds of flow onset. The mechanically activated cation channel Piezo1 has recently been implicated due to its involvement in mediating early responses, such as calcium and ATP release. Here, we investigate the role of Piezo1 in rapid shear stress-induced Gαq/11 activation. We show that flow-induced dissociation of Gαq/11 from PECAM-1 in ECs at 15 s is abrogated by BIM-46187, a selective inhibitor of Gαq/11 activation, suggesting that Gαq/11 activation is required for PECAM-1/Gαq/11 dissociation. Although siRNA knockdown of Piezo1 caused a dramatic decrease in PECAM-1/Gαq/11 association in the basal condition, it had no effect on flow-induced dissociation. Interestingly, siRNA knockdown of Piezo1 caused a marked decrease in PECAM-1 expression. Additionally, selective blockade of Piezo1 with ion channel inhibitors had no effect on flow-induced PECAM-1/Gαq/11 dissociations. Lastly, flow onset caused increased association of Gβ1 with Piezo1 as well as with the p101 subunit of phosphoinositide 3-kinase, which were both blocked by the Gβγ inhibitor gallein. Together, our results indicate that flow-induced activation of Piezo1 is not upstream of G protein activation.

Mechanoresponsive self-growing hydrogels inspired by muscle training

Living tissues, such as muscle, autonomously grow and remodel themselves to adapt to their surrounding mechanical environment through metabolic processes. By contrast, typical synthetic materials cannot grow and reconstruct their structures once formed. We propose a strategy for developing “self-growing” polymeric materials that respond to repetitive mechanical stress through an effective mechanochemical transduction. Robust double-network hydrogels provided with a sustained monomer supply undergo self-growth, and the materials are substantially strengthened under repetitive loading through a structural destruction-reconstruction process. This strategy also endows the hydrogels with tailored functions at desired positions by mechanical stamping. This work may pave the way for the development of self-growing gel materials for applications such as soft robots and intelligent devices.

The structural kinetics of switch-1 and the neck linker explain the functions of kinesin-1 and Eg5

Kinesins perform mechanical work to power a variety of cellular functions, from mitosis to organelle transport. Distinct functions shape distinct enzymologies, and this is illustrated by comparing kinesin-1, a highly processive transport motor that can work alone, to Eg5, a minimally processive mitotic motor that works in large ensembles. Although crystallographic models for both motors reveal similar structures for the domains involved in mechanochemical transduction—including switch-1 and the neck linker—how movement of these two domains is coordinated through the ATPase cycle remains unknown. We have addressed this issue by using a novel combination of transient kinetics and time-resolved fluorescence, which we refer to as “structural kinetics,” to map the timing of structural changes in the switch-1 loop and neck linker. We find that differences between the structural kinetics of Eg5 and kinesin-1 yield insights into how these two motors adapt their enzymologies for their distinct functions.