Confinement hinders motility by inducing RhoA-mediated nuclear influx, volume expansion, and blebbing

Panagiotis Mistriotis, Emily O. Wisniewski, Kaustav Bera, Jeremy Keys, Yizeng Li, Soontorn Tuntithavornwat, Robert A. Law, Nicolas A. Perez-Gonzalez, Eda Erdogmus, Yuqi Zhang, Runchen Zhao, Sean X. Sun, Petr Kalab, Jan Lammerding, Konstantinos Konstantopoulos

Research output: Contribution to journalArticle

Abstract

Cells migrate in vivo through complex confining microenvironments, which induce significant nuclear deformation that may lead to nuclear blebbing and nuclear envelope rupture. While actomyosin contractility has been implicated in regulating nuclear envelope integrity, the exact mechanism remains unknown. Here, we argue that confinement-induced activation of RhoA/ myosin-II contractility, coupled with LINC complex-dependent nuclear anchoring at the cell posterior, locally increases cytoplasmic pressure and promotes passive influx of cytoplasmic constituents into the nucleus without altering nuclear efflux. Elevated nuclear influx is accompanied by nuclear volume expansion, blebbing, and rupture, ultimately resulting in reduced cell motility. Moreover, inhibition of nuclear efflux is sufficient to increase nuclear volume and blebbing on two-dimensional surfaces, and acts synergistically with RhoA/myosin-II contractility to further augment blebbing in confinement. Cumulatively, confinement regulates nuclear size, nuclear integrity, and cell motility by perturbing nuclear flux homeostasis via a RhoA-dependent pathway.

Original languageEnglish (US)
Pages (from-to)4093-4111
Number of pages19
JournalJournal of Cell Biology
Volume218
Issue number12
DOIs
StatePublished - Dec 2 2019

ASJC Scopus subject areas

  • Cell Biology

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    Mistriotis, P., Wisniewski, E. O., Bera, K., Keys, J., Li, Y., Tuntithavornwat, S., Law, R. A., Perez-Gonzalez, N. A., Erdogmus, E., Zhang, Y., Zhao, R., Sun, S. X., Kalab, P., Lammerding, J., & Konstantopoulos, K. (2019). Confinement hinders motility by inducing RhoA-mediated nuclear influx, volume expansion, and blebbing. Journal of Cell Biology, 218(12), 4093-4111. https://doi.org/10.1083/JCB.201902057