Molecular consequences of microtubule bending in living cells

Project Summary/Abstract The overarching goal of the Nihongaki group is to decipher the molecular consequences and functional implications of microtubule bending in living cells. We will achieve this by creating innovative molecular tools that can manipulate target molecular processes with precision. Microtubules play a crucial role in vital cellular processes, including cell division, cell migration, and cell polarity. Consequently, defects in microtubules, such as mutations in proteins associated with microtubules, are often linked to a variety of human diseases, including cardiovascular and neurological disorders. At a molecular level, microtubules are cylindrical filaments made up of alpha and beta tubulin dimers. Because of their high rigidity, microtubules reconstructed in vitro grow in a straight line and are readily broken by mechanical stress. In contrast, cellular microtubules are often bent without significant breakage, and the molecular consequences of microtubule bending in living cells remain largely elusive. Does microtubule bending damage the lattice of microtubules in cells? How do cells grant microtubules mechanical resilience in response to their bending? Is microtubule damage induced by bending stress repaired? To address these fundamental questions, our research program for the next five years will concentrate on investigating the molecular events occurring on bent microtubules in living cells. This will be facilitated by the development and implementation of a novel genetically encoded tool for inducible control of microtubule bending. By combining this microtubule bending technique with fluorescence microscopy, genetic and pharmacological perturbation, and other molecular tools, we will comprehensively illuminate the molecular response to microtubule bending in living cells: curvature-induced microtubule damage, local microtubule protection by tubulin acetylation, and lateral repair by fresh tubulin incorporation. This research will provide new mechanistic insights into microtubule maintenance in living cells, potentially leading to novel therapeutic strategies for microtubule-related diseases.