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

Abstract

SummaryGenetic 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.

Cellular functions of the ADF/cofilin family at a glance

“…The effects are less prominent when ADF is depleted alone and are most severe after co-depletion of both ADF and CFL1, implying functional redundancy in this cellular context (Hotulainen et al, 2005;Wiggan et al, 2012). Increased contractility following ADF and CFL1 co-depletion has also recently been reported, where it was shown that a similar mechanism involving tight control of contractile actin fibres by cofilins regulates nuclear architecture and ultimately cell viability (see below) (Kanellos et al, 2015). Interestingly, another consequence of dysregulation of the actin cytoskeleton occurs during neuritogenesis.…”

“…Moreover, double depletion of ADF and CFL1 (but not single deletion) in the skin epithelium of adult mice also leads to loss of tissue homeostasis, with extensive epidermal thickening, aberrant cell morphology with loss of cell-cell contacts, hyperproliferation and a pronounced accumulation of filamentous actin (Kanellos et al, 2015), indicating that there is some functional redundancy between ADF and CFL1 in some tissue contexts.…”

“…Furthermore, lack of a readily available antibody against CFL2 has delayed deeper understanding of the role of this isoform. We now know that many tissues express all three isoforms, including oligodendrocytes, keratinocytes and cancerous tissue of non-muscle origin (Kanellos et al, 2015;Zuchero et al, 2015), and that CFL2 is a major constituent in human peritoneal mesothelial cells (Herzog et al, 2015). It is possible that tissues that express multiple isoforms might fine tune their expression levels individually in order to tightly control the rates of actin turnover, whereas the types of accessory protein that decorate actin filaments and the expression patterns of cofilin ancillary proteins (see Box 2) modify their efficiency.…”

“…The depletion of both ADF and CFL1 leads to severe perturbation of cellular and adult tissue homeostasis, which is marked by the uncontrolled assembly of contractile actin filaments and consequent increase in tension that promotes nuclear deformation and loss of cell viability (Kanellos et al, 2015). A specialized subset of contractile actin fibres (which are tethered into focal adhesions) pass over the nucleus and regulate nuclear shape -these are collectively termed the 'actin cap' (Khatau et al, 2009;Kim et al, 2012).…”

“…The linker of nucleoskeleton and cytoskeleton (LINC) complex, which localizes to the nuclear envelope, physically connects these actin cap fibres with the nuclear lamina (reviewed in Starr and Fridolfsson, 2010). Disruption of this LINC-complex-mediated connection relieves nuclei from the increased forces exerted on them by the aberrant tensile filaments that arise after ADF and CFL1 depletion, and restores nuclear integrity and normal shape (Kanellos et al, 2015). This implies that the actin cap fibres are regulated by cofilins in cells and that this regulation is crucial for nuclear positioning and migration, as well as probably all the cellular features and responses that are controlled by the link between the actin cytoskeleton and the nuclear envelope (Starr and Fridolfsson, 2010) (see poster).…”