Cofilin: a redox sensitive mediator of actin dynamics during T‐cell activation and migration

Abstract

Cofilin is an actin-binding protein that depolymerizes and/or severs actin filaments. This dual function of cofilin makes it one of the major regulators of actin dynamics important for T-cell activation and migration. The activity of cofilin is spatio-temporally regulated. Its main control mechanisms comprise a molecular toolbox of phospho-, phospholipid, and redox regulation. Phosphorylated cofilin is inactive and represents the dominant cofilin fraction in the cytoplasm of resting human T cells. A fraction of dephosphorylated cofilin is kept inactive at the plasma membrane by binding to phosphatidylinositol 4,5-bisphosphate. Costimulation via the T-cell receptor/CD3 complex (signal 1) together with accessory receptors (signal 2) or triggering through the chemokine SDF1α (stromal cell-derived factor 1α) induce Ras-dependent dephosphorylation of cofilin, which is important for immune synapse formation, T-cell activation, and T-cell migration. Recently, it became evident that cofilin is also highly sensitive for microenvironmental changes, particularly for alterations in the redox milieu. Cofilin is inactivated by oxidation, provoking T-cell hyporesponsiveness or necrotic-like programmed cell death. In contrast, in a reducing environment, even phosphatidylinositol 4,5-bisphosphate -bound cofilin becomes active, leading to actin dynamics in the vicinity of the plasma membrane. In addition to the well-established three signals for T-cell activation, this microenvironmental control of cofilin delivers a modulating signal for T-cell-dependent immune reactions. This fourth modulating signal highly impacts both initial T-cell activation and the effector phase of T-cell-mediated immune responses.

Dose- and ApoE Isoform-Dependent Cognitive Injury after Cranial56Fe Irradiation in Female Mice

“…The protein cofilin, which regulates the actin filament system in dendrites and spines, has been shown to be redox-sensitive (Samstag et al 2013), and cofilin and its regulatory network have recently been shown to be highly responsive to irradiation (cf. below, ).…”

“…Notably, cofilin organizes surface receptor complexes in the "immunological synapse". Its activity may polymerize or depolymerize actin depending on the availability of G-actin, and cofilin activity is under direct redox control, which implicates it in oxidative disturbances of actin dynamics (Samstag et al 2013). This may render it acutely sensitive to radiation or to persistent oxidative stress.…”

Myeloperoxidase Attenuates Pathogen Clearance during Plasmodium yoelii Nonlethal Infection

“…Evidence indicates that ROS generated by the myeloperoxidase-hydrogen peroxide system could lead to a suppression of T cells. Suppression (52)(53)(54) or induced apoptosis (55) of T cells by an oxidative environment have been described recently. Additionally, studies showed that MPO, or its products, could modulate the initiation of the T cell response via suppression of dendritic cells (36,56).…”

Redox regulation of cytoskeletal dynamics during differentiation and de-differentiation

“…Moreover, myosin cysteins are susceptible to S-glutathionylation modulating its ATPase activity [91]. Cofilin controls stability of F-actin and, depending on its oxidation state, actin dynamics are impaired [92].…”

“…Cofilin activity can be regulated via reactive oxygen species through redox-sensitive proteins and signalling cascades, including the activities of RhoA [98], PKD1 [99], and 14-3-3 zeta [100]. Moreover, redox regulation of specific cysteine residues of cofilin is emerging as another form of post-translational regulation, also assuring rapid and spatial control of protein function and cytoskeleton action towards distinct stimuli [92]. The human, non-muscle isoform cofilin-1 contains four cysteine residues at the positions 39, 80, 139 and 147; with 39 and 80 being located inside the protein and 139 and 147 being located on the surface of the protein [101].…”