NPCvalve · Beyond nucleocytoplasmic transport – Nuclear pores as self-regulating valves for flux across the nuclear envelope

Nuclear pore complexes (NPCs) are fundamental components of all eukaryotic cells. They fuse the inner and outer nuclear membranes and form channels across the nuclear envelope. Their canonical function as gatekeepers of the nucleus and facilitators of nucleocytoplasmic exchange is well established. I hypothesize that NPCs fulfil yet another fundamental function as self-regulating valves for flux across the nuclear envelope that occurs in response to mechanical stress. This yet underappreciated function may be of utmost importance to prevent rupture of the nuclear envelope and thus to protect the genomic integrity in cells that are exposed to mechanical stress. I present preliminary data indicating that NPC conformation responds to mechanical force exerted onto the nuclear envelope with dilation and constriction. Cryo-electron tomography, live cell imaging, and genetic perturbation will be used jointly with structural modelling to investigate on a holistic scale how NPC diameter and nuclear envelope tension impact on flux across the nuclear envelope. In the proposed project I will demonstrate that besides their known function as transport channels the NPCs serve an important role as shock adsorbers for mechanical stress impacting the nucleus. The research proposed here will enhance our understanding of how cells deal with acute mechanical stress which is relevant for cell migration, metastasis, mechanically active tissues and cell differentiation.