The mechanically activated Piezo channel plays a versatile role in conferring mechanosensitivity to various cell types. The homotrimeric Piezo channel resembles a gigantic three-bladed propeller-like structure, in which the non-planar transmembrane regions of 114 transmembrane segments in total are collectively curved into a unique nano-bowl shape. On the basis of the signature bowl-shaped feature of the Piezo channel-membrane system and previous electrophysiological characterizations, Piezo channels have been proposed to adopt a force-from-lipids gating mechanism to sense changes in local curvature and membrane tension. However, how it incorporates its intrinsic mechanosensitivity and cellular components to effectively sense long-range mechanical perturbation across a cell remains elusive. Here we show that Piezo channels are biochemically and functionally tethered to the actin cytoskeleton via the cadherin-β-catenin mechanotransduction complex, whose perturbation significantly impairs Piezo-mediated responses. Mechanistically, the adhesive extracellular domain of E-cadherin interacts with the cap domain of Piezo1 that controls the transmembrane gate, while its cytosolic tail might interact with the cytosolic domains of Piezo1 that are in close proximity to its intracellular gates, allowing a direct focus of adhesion-cytoskeleton-transmitted force for gating. Specific disruption of the intermolecular interactions prevents cytoskeleton-dependent gating of Piezo1. Thus, we propose a force-from-filament model to complement the previously suggested force-from-lipids model for mechanogating of Piezo channels, enabling them to serve as versatile and tunable mechanotransducers.
 

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