Cell migration requires cells to navigate crowded three-dimensional environments, forcing them to squeeze through narrow spaces. This presents a mechanical challenge in particular for the nucleus, because it is large and stiff. Cells must correctly position and protect the nucleus while coordinating actomyosin contractility to move through confined spaces. Despite the prevalence of compression as a mechanical input in cellular environments, our understanding of how cells sense and respond to such forces remains limited. Ju et al. now show that microtubules act as a mechanostat, by adapting their biomechanical properties to resist compressive forces and promote contractility.

By tracking endogenously tagged microtubules in highly migratory melanoma cells, they discovered that microtubules initially organize into a cage-like structure encasing the nucleus as the leading edge of the cell moves through a narrow space. This configuration forces microtubules into a highly curved conformation, making them prone to damage and prompting the recruitment of cytoplasmic linker-associated proteins (CLASPs). CLASPs are known rescue factors that support microtubule growth and repair in part by enhancing acetylation of lysine 40 (Lys40) of α-tubulin, a modification that increases microtubule stability and flexibility under mechanical stress. Loss of CLASPs slowed migration through microfabricated confinement channels and caused the rupture of migrating cells, highlighting the necessity of microtubule repair for successful migration through tight spaces.