BPS2026 – PIEZO channel auxiliary subunits in sensory and non-sensory cells

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.