Redox Regulation of the Actin Cytoskeleton in Cell Migration and Adhesion: On the Way to a Spatiotemporal View

Abstract

The actin cytoskeleton of eukaryotic cells is a dynamic, fibrous network that is regulated by the concerted action of actin-binding proteins (ABPs). In particular, rapid polarization of cells in response to internal and external stimuli is fundamental to cell migration and invasion. Various isoforms of ABPs in different tissues equip cells with variable degrees of migratory and adhesive capacities. In addition, regulation of ABPs by posttranslational modifications (PTM) is pivotal to the rapid responsiveness of cells. In this context, phosphorylation of ABPs and its functional consequences have been studied extensively. However, the study of reduction/oxidation (redox) modifications of oxidation-sensitive cysteine and methionine residues of actin, ABPs, adhesion molecules, and signaling proteins regulating actin cytoskeletal dynamics has only recently emerged as a field. The relevance of such protein oxidations to cellular physiology and pathophysiology has remained largely elusive. Importantly, studying protein oxidation spatiotemporally can provide novel insights into localized redox regulation of cellular functions. In this review, we focus on the redox regulation of the actin cytoskeleton, its challenges, and recently developed tools to study its physiological and pathophysiological consequences.

Cofilin and Actin Dynamics: Multiple Modes of Regulation and Their Impacts in Neuronal Development and Degeneration

“…Understanding the coordinated regulation of this multitude of proteins has become more complex due to the discovery of additional posttranslational modifications of cytoplasmic actin [182], including oxidation/reduction (redox regulation and S-glutathionylation) [121,183], N-terminal arginylation [184], and lysine acetylation [185]. As an example, a specific plasma membrane enzyme called Mical, an NADPH-dependent oxido-reductase [186,187], oxidizes F-actin on specific methionine residues (M44 and M47), which enhances the ability of cofilin to depolymerize these filaments at a faster rate [188]. Whether or not this enhanced actin turnover is the major cellular function of Mical still needs to be established since many other cortical actininteracting proteins have yet to be studied in the context of oxidized actin.…”

Hijacked Immune Cells in the Tumor Microenvironment: Molecular Mechanisms of Immunosuppression and Cues to Improve T Cell-Based Immunotherapy of Solid Tumors

“…Conversely, functions of T cells, NK cells, and potentially B cells, which have a lower antioxidant capacity, are strongly downmodulated by high ROS levels in the TME. In this context, we have previously shown that proteins modulating actin cytoskeletal dynamics (cofilin and L-plastin) are highly oxidized in T cells under pro-oxidative conditions [ 34 , 35 , 219 , 220 ]. Since these proteins regulate various T cell functions, including T cell migration, invasion, and cytotoxicity, the oxidation of such proteins can partly explain the loss of T cell functions in a pro-oxidative TME.…”

Reactive oxygen species (ROS) constitute an additional player in regulating epithelial development

“…The effects of ROS on actin are well established, both in-vitro and in-vivo (reviewed in [53][54][55][56] ). Best studied are modifications of β-actin by ROS that occur preferentially at one of its cysteine residues, Cys-374, which results in formation of disulphide bonds between two actin monomers.…”