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

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. [Display omitted] •Loss of both ADF and CFL1 severely perturbs adult tissue homeostasis•ADF/CFL1 loss results in uncontrolled accumulation of contractile actin stress fibers•Acto-myosin tension causes nuclear deformation mediated by the LINC complex•ADF and CFL1 control nuclear integrity and cell survival via actin dynamics The filament-severing proteins ADF and CFL1 mediate actin stress fiber turnover. Kanellos et al. find that their co-depletion leads to uncontrolled accumulation of contractile actin filaments, which, via the LINC complex, physically disrupt the nucleus and cause loss of cell and tissue viability.