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

J Cell Biol. 2019 Dec 2;218(12):4093-4111. doi: 10.1083/jcb.201902057. Epub 2019 Nov 5.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Actin Cytoskeleton / metabolism
  • Actins / metabolism
  • Actomyosin / metabolism
  • Cell Line, Tumor
  • Cell Movement
  • Cell Nucleus / metabolism
  • Cytoplasm / metabolism
  • Fluorescence Resonance Energy Transfer
  • Homeostasis
  • Humans
  • Myosin Type II / metabolism*
  • Nuclear Envelope / metabolism
  • Tumor Microenvironment
  • rhoA GTP-Binding Protein / metabolism*

Substances

  • Actins
  • RHOA protein, human
  • Actomyosin
  • Myosin Type II
  • rhoA GTP-Binding Protein