TY - JOUR
T1 - Confinement hinders motility by inducing RhoA-mediated nuclear influx, volume expansion, and blebbing
AU - Mistriotis, Panagiotis
AU - Wisniewski, Emily O.
AU - Bera, Kaustav
AU - Keys, Jeremy
AU - Li, Yizeng
AU - Tuntithavornwat, Soontorn
AU - Law, Robert A.
AU - Perez-Gonzalez, Nicolas A.
AU - Erdogmus, Eda
AU - Zhang, Yuqi
AU - Zhao, Runchen
AU - Sun, Sean X.
AU - Kalab, Petr
AU - Lammerding, Jan
AU - Konstantopoulos, Konstantinos
N1 - Funding Information:
U54CA210184 to J. Lammerding), the U.S. Department of Defense Breast Cancer Research Program (Breakthrough Award BC150580 to J. Lammerding), and the National Science Foundation (CAREER Award CBET-1254846 to J. Lammerding). Some of the imaging data were acquired through the Cornell University Biotechnology Resource Center, with NYSTEM (CO29155) and National Institutes of Health (S10OD018516) funding for the shared Zeiss LSM880 confocal/multiphoton microscope. This work received additional support from the Knight@KIC 2018-2019 Graduate Fellowship (to J. Keys). The authors declare no competing financial interests.
Funding Information:
This work was supported, in part, by a National Science Foundation Graduate Research Fellowship (DGE-1746891 to E.O. Wisniewski), an American Heart Association Postdoctoral Fellowship (18POST34080345 to P. Mistriotis), and grants from the National Institutes of Health (R01CA183804 to K. Konstantopoulos, R01CAGM114675 to S.X. Sun and K. Konstantopoulos, U54CA210173 to K. Konstantopoulos and S.X. Sun, and R01HL082792 and
Publisher Copyright:
© 2019 Mistriotis et al.
PY - 2019/12/2
Y1 - 2019/12/2
N2 - 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.
AB - 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.
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U2 - 10.1083/JCB.201902057
DO - 10.1083/JCB.201902057
M3 - Article
C2 - 31690619
AN - SCOPUS:85076066310
SN - 0021-9525
VL - 218
SP - 4093
EP - 4111
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 12
ER -