Piezo Mechanosensory Channels Control Centriole Engagement via Calcium Signaling at the Centrosome

Abstract

Mechanotransduction is a process by which mechanical stimuli are converted into biochemical signals in cells to elicit different physiological functions, including embryogenesis, hearing, touch and muscle contractility. Piezo1 and 2 are evolutionarily conserved mechanosensory cation channels known to function on the cell surface by responding to external pressure and transducing a mechanically activated ion current. Piezo proteins have overlapping but distinct expression patterns in tissues and cells, and therefore exhibit both common and unique biological functions. Both gain- and loss-of-function PIEZO1and PIEZO2 mutations are associated with a number of severe human diseases.The majority of studies have focused on the Piezo mechanosensor function on the cell membrane, with transduction of MA currents to the cytoplasm in response to extracellular forces. Here, we show in myoblasts and multiple other cell types that Piezo proteins are also expressed intracellularly at the centrosome. Both Piezo loss-of-function and Piezo1 activation produce supernumerary centrosomes due to inappropriate centriole disengagement, leading to multi-polar spindles and a cell cycle defect. Some of the free centrioles migrate to the cell periphery to form supernumerary basal bodies and cilia. We further show that perturbations in Piezo modulate Calcium flux at centrosomes, indicated by a Calcium reporter, and that photoactivation of a caged Piezo1 agonist at centrosomes lead to rapid centriole disengagement. Thus, we suggest that mechanotransduction by Piezo in peri-centrosomal pool regulates centriole engagement by maintaining peri-centrosomal Calcium within a defined range, likely through sensing cell intrinsic forces from microtubules.