Title: Piezo Mechanosensory channels regulate centrosome integrity and mitotic entry

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 be responsible for sensing mechanical stimuli and transducing a mechanically activated ion current, on the cell membrane. Piezo channels are widely expressed, and play important roles in developmental and homeostatic processes. 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 PIEZO1 and PIEZO2 mutations are associated with several severe human diseases, such as anemia, musculoskeletal disorders, and cancer. In addition, Piezo1 was shown to regulate the regenerative capacity of muscle stem cells. The majority of studies have focused on the Piezo mechanosensory function on the cell membrane, with transduction of currents to the cytoplasm in response to extracellular forces. Here, we show in myoblasts and multiple other cell types that Piezo proteins also exhibit concentrated intracellular localization at centrosomes. Both Piezo loss-of-function and Piezo1 activation by the small molecule Yoda1 produce supernumerary centrosomes due to premature centriole disengagement leading to multi-polar spindles, and mitotic delay. We further show that perturbations in Piezo modulate Ca2+ flux at centrosomes, indicated by a Ca2+ reporter and that photoactivation of a caged Piezo1 agonist at centrosomes leads to rapid centriole disengagement. Moreover, the inhibition of Polo-like kinase 1 eliminates Yoda1-induced centriole disengagement. Thus, we suggest that mechanotransduction by Piezo in the peri-centrosomal pool regulates centriole engagement by maintaining peri-centrosomal Ca2+ within a defined range, likely through sensing cell intrinsic forces from microtubules. Thus, Piezo proteins may represent an important new class of intracellular mechanotransducers.

Biography:

David is a structural and cell biologist, currently an instructor at Harvard Medical School. She completed her graduate studies at the Technion, Israel Institute of Technology. For her Postdoctoral training, Liron joined the structural immunology lab of Prof. Hao Wu at the Harvard Medical School and was awarded the Cancer Research Institute postdoctoral fellowship. Liron obtained in-depth training in cryoelectron microscopy (cryo-EM) and cell biology including cellular imaging and other cutting-edge techniques and followed her passion to investigate large and challenging molecular assemblies and membrane proteins in the field of immunology, cancer research and mechanotransduction investigating piezo channels in myoblasts.