ADF and Cofilin1 Control Actin Stress Fibers, Nuclear Integrity, and Cell Survival

Cell Rep. 2015 Dec 1;13(9):1949-64. doi: 10.1016/j.celrep.2015.10.056. Epub 2015 Nov 19.

Abstract

Genetic co-depletion of the actin-severing proteins ADF and CFL1 triggers catastrophic loss of adult homeostasis in multiple tissues. There is impaired cell-cell adhesion in skin keratinocytes with dysregulation of E-cadherin, hyperproliferation of differentiated cells, and ultimately apoptosis. Mechanistically, the primary consequence of depleting both ADF and CFL1 is uncontrolled accumulation of contractile actin stress fibers associated with enlarged focal adhesions at the plasma membrane, as well as reduced rates of membrane protrusions. This generates increased intracellular acto-myosin tension that promotes nuclear deformation and physical disruption of the nuclear lamina via the LINC complex that normally connects regulated actin filaments to the nuclear envelope. We therefore describe a pathway involving the actin-severing proteins ADF and CFL1 in regulating the dynamic turnover of contractile actin stress fibers, and this is vital to prevent the nucleus from being damaged by actin contractility, in turn preserving cell survival and tissue homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / metabolism*
  • Actin-Related Protein 3 / antagonists & inhibitors
  • Actin-Related Protein 3 / genetics
  • Actin-Related Protein 3 / metabolism
  • Animals
  • Cadherins / metabolism
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Survival
  • Cells, Cultured
  • Cofilin 1 / antagonists & inhibitors
  • Cofilin 1 / genetics
  • Cofilin 1 / metabolism*
  • Destrin / deficiency
  • Destrin / genetics
  • Destrin / metabolism*
  • Focal Adhesions / metabolism
  • Formins
  • Keratinocytes / cytology
  • Keratinocytes / metabolism
  • Mice
  • Mice, Knockout
  • Microtubule-Associated Proteins / antagonists & inhibitors
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • NADPH Dehydrogenase / antagonists & inhibitors
  • NADPH Dehydrogenase / genetics
  • NADPH Dehydrogenase / metabolism
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Nuclear Envelope / metabolism
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Skin / metabolism
  • Skin / pathology

Substances

  • Actin-Related Protein 3
  • Actr3 protein, mouse
  • Cadherins
  • Carrier Proteins
  • Cfl1 protein, mouse
  • Cofilin 1
  • Destrin
  • Diap1 protein, mouse
  • Dstn protein, mouse
  • Formins
  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • RNA, Small Interfering
  • Syne2 protein, mouse
  • Dia2 protein, mouse
  • NADPH Dehydrogenase