Compression-dependent microtubule reinforcement enables cells to navigate confined environments

Cells migrating through complex three-dimensional environments experience considerable physical challenges, including tensile stress and compression. To move, cells need to resist these forces while also squeezing the large nucleus through confined spaces. This requires highly coordinated cortical c...

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Bibliographic Details
Published in:Nature cell biology Vol. 26; no. 9; pp. 1520 - 1534
Main Authors: Ju, Robert J., Falconer, Alistair D., Schmidt, Christanny J., Enriquez Martinez, Marco A., Dean, Kevin M., Fiolka, Reto P., Sester, David P., Nobis, Max, Timpson, Paul, Lomakin, Alexis J., Danuser, Gaudenz, White, Melanie D., Haass, Nikolas K., Oelz, Dietmar B., Stehbens, Samantha J.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 01.09.2024
Nature Publishing Group
Subjects:
631/80/128/1653
631/80/84/2336
Actomyosin
Actomyosin - metabolism
Animals
Biology
Biomedical and Life Sciences
Cancer Research
Cell activation
Cell Biology
Cell migration
Cell Movement
Cell Nucleus - metabolism
Cells
Cellular structure
Compression
Confined spaces
Contractility
Developmental Biology
Humans
Life Sciences
Localization
Mechanotransduction, Cellular
Mice
Microfilament Proteins
Microtubule-Associated Proteins - genetics
Microtubule-Associated Proteins - metabolism
Microtubules
Microtubules - metabolism
Nuclei (cytology)
Polymers
Proteins
Signal transduction
Stem Cells
Stress, Mechanical
Tensile stress
Three dimensional motion
ISSN:1465-7392, 1476-4679, 1476-4679
Online Access:Get full text
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Summary:Cells migrating through complex three-dimensional environments experience considerable physical challenges, including tensile stress and compression. To move, cells need to resist these forces while also squeezing the large nucleus through confined spaces. This requires highly coordinated cortical contractility. Microtubules can both resist compressive forces and sequester key actomyosin regulators to ensure appropriate activation of contractile forces. Yet, how these two roles are integrated to achieve nuclear transmigration in three dimensions is largely unknown. Here, we demonstrate that compression triggers reinforcement of a dedicated microtubule structure at the rear of the nucleus by the mechanoresponsive recruitment of cytoplasmic linker-associated proteins, which dynamically strengthens and repairs the lattice. These reinforced microtubules form the mechanostat: an adaptive feedback mechanism that allows the cell to both withstand compressive force and spatiotemporally organize contractility signalling pathways. The microtubule mechanostat facilitates nuclear positioning and coordinates force production to enable the cell to pass through constrictions. Disruption of the mechanostat imbalances cortical contractility, stalling migration and ultimately resulting in catastrophic cell rupture. Our findings reveal a role for microtubules as cellular sensors that detect and respond to compressive forces, enabling movement and ensuring survival in mechanically demanding environments. Ju et al. show that during three-dimensional cell migration, compression recruits cytoplasmic linker-associated proteins to microtubules; these stabilized microtubules then coordinate nuclear positioning and contractility in confined migration.
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ISSN:1465-7392
1476-4679
1476-4679
DOI:10.1038/s41556-024-01476-x