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J Cell Biol. 2019 Nov 5. pii: jcb.201902057. doi: 10.1083/jcb.201902057. [Epub ahead of print]

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

Author information

1
Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD.
2
Johns Hopkins Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD.
3
Meinig School of Biomedical Engineering and Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY.
4
Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD.
5
Department of Mechanical Engineering, Kennesaw State University, Marietta, GA.
6
Johns Hopkins Physical Sciences-Oncology Center, Johns Hopkins University, Baltimore, MD.
7
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD.
8
Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD konstant@jhu.edu.
9
Department of Oncology, Johns Hopkins University, Baltimore, MD.
#
Contributed equally

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.

PMID:
31690619
DOI:
10.1083/jcb.201902057

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