PIEZO ion channels are molecular sensors of mechanical forces. They are ubiquitously expressed throughout all organ systems and play key roles in decoding mechanical cues across sensory and non-sensory cells. Despite their large size, ubiquitous expression and physiological importance, few reproducible PIEZO channel binding proteins have emerged. Using affinity capture mass spectrometry coupled with a fibroblast-centric view of PIEZO channel mechanosensing we identified MyoD-family inhibitor domain containing proteins, MDFI and MDFIC, as PIEZO channel auxiliary subunits that potently regulate channel function. We show that these proteins, along with an uncharacterized gene, Mdfic2 , modulate endogenous PIEZO1/2 currents across both sensory and non-sensory cell types. Specifically, these proteins complex with PIEZO1/2 changing their mechanosensitivity and inactivation kinetics, converting them into slowly inactivating, high-threshold mechanoreceptors. Extensive cryo-EM based characterization reveals a conserved PIEZO1/2 binding pocket for all these auxiliary subunits that may ultimately provide the basis for rational design of PIEZO-targeted therapeutics. Interestingly, MyoD-family inhibitor proteins are canonically known as transcription factor binding proteins. This unique dual functionality: modulating channel function and transcription factor localization, positions these proteins as key molecular bridges between mechanotransduction and gene expression. The partnership of PIEZOs and MyoD-family inhibitor proteins thus offers a way to broaden our understanding of how mechanical inputs drive cellular changes at the transcriptional level.
Charles D. Cox (Sun,) studied this question.