Piezo mechanosensory channels regulate centrosome integrity

Abstract

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 Ca2+ current. Here we show that both Piezo1 and 2 also exhibit concentrated intracellular localization at centrosomes. Both Piezo1 and 2 loss-of-function and Piezo1 activation by the small molecule Yoda1 produced supernumerary centrosomes due to inappropriate centriole disengagement. Using a centrosome-localized GCaMP Ca2+-sensitive reporter, we show that perturbations in Piezo modulate Ca2+ local concentration at centrosomes. We designed a photoactivable Yoda1 analog (caged-Yoda1) and revealed that its photoactivation specifically at centrosomes leads to rapid premature centriole disengagement within minutes. We identified the sorting nexin Snx5, which is involved in endocytic uptake and trafficking, as a protein-interactor with the conserved Piezo C-terminal domain, and Snx5 also co-localizes with Piezo1 and 2 at centrosomes. Moreover, inhibition of Polo-like-kinase 1 (PLK1) abolishes Yoda1-induced centriole disengagement. Collectively, these data suggest that Piezo1 and 2 in pericentrosomal endosomes control centrosome integrity, likely by maintaining local Ca2+ within a defined range through mechanotransduction of cell intrinsic forces from microtubules.

Microglial Piezo1 mechanosensitive channel as a therapeutic target in Alzheimer’s disease

“…Unlike Yoda1, Jedi1/2 activation occurs on the extracellular side of the channel's three-bladed propeller-like structure (Wang et al, 2018). Furthermore, Jedi1 and Jedi2 do not cross the cell membrane, and therefore only activate Piezo1 from the extracellular side (David et al, 2023). Both Jedi1 and Jedi2 are typically used in concentrations ranging between 5 and 200 µM (Wang et al, 2018).…”