Cofilin: a redox sensitive mediator of actin dynamics during T‐cell activation and migration
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Summary 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/ CD 3 complex (signal 1) together with accessory receptors (signal 2) or triggering through the chemokine SDF 1α (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.Keywords:
Cofilin
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Actin remodeling
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Actin interacting protein 1 (Aip1) is a conserved component of the actin cytoskeleton first identified in a two-hybrid screen against yeast actin. Here, we report that Aip1p also interacts with the ubiquitous actin depolymerizing factor cofilin. A two-hybrid–based approach using cofilin and actin mutants identified residues necessary for the interaction of actin, cofilin, and Aip1p in an apparent ternary complex. Deletion of the AIP1 gene is lethal in combination with cofilin mutants or act1-159, an actin mutation that slows the rate of actin filament disassembly in vivo. Aip1p localizes to cortical actin patches in yeast cells, and this localization is disrupted by specific actin and cofilin mutations. Further, Aip1p is required to restrict cofilin localization to cortical patches. Finally, biochemical analyses show that Aip1p causes net depolymerization of actin filaments only in the presence of cofilin and that cofilin enhances binding of Aip1p to actin filaments. We conclude that Aip1p is a cofilin-associated protein that enhances the filament disassembly activity of cofilin and restricts cofilin localization to cortical actin patches.
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Summary The actin cytoskeleton provides a dynamic framework to support membrane organization and cellular signaling events. The importance of actin in T cell function has long been recognized to go well beyond the maintenance of cell morphology and transport of proteins. Over the past several years, our understanding of actin in T cell activation has expanded tremendously, in part owing to the development of methods and techniques to probe the complex interplay between actin and T cell signaling. On the one hand, biochemical methods have led to the identification of many key cytoskeleton regulators and new signaling pathways, whereas, on the other, the combination of advanced imaging techniques and physical characterization tools has allowed the spatiotemporal investigation of actin in T cell signaling. All those studies have made a profound impact on our understanding of the actin cytoskeleton in T cell activation. Many previous reviews have focused on the biochemical aspects of the actin cytoskeleton. However, here we will summarize recent studies from a biophysical perspective to explain the mechanistic role of actin in modulating T cell activation. We will discuss how actin modulates T cell activation on multiple time and length scales. Specifically, we will reveal the distinct roles of the actin filaments in facilitating TCR triggering, orchestrating ‘signalosome’ assembly and transport, and establishing protein spatial organization in the immunological synapse.
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Abstract Dynamic rearrangements of the actin cytoskeleton are crucial for the function of numerous cellular elements including T lymphocytes. They are required for migration of T lymphocytes through the body to scan for the presence of antigens, as well as for the formation and stabilization of the immunological synapse at the interface between antigen-presenting cells and T lymphocytes. Supramolecular activation clusters within the immunological synapse play an important role for the initiation of T cell responses and for the execution of T cell effector functions. In addition to the T cell receptor/CD3 induced actin nucleation via Wasp/Arp2/3-activation, signals through accessory receptors of the T cell (i.e., costimulation) regulate actin cytoskeletal dynamics. In this regard, the actin-binding proteins cofilin and L-plastin represent prominent candidates linking accessory receptor stimulation to the rearrangement of the actin cytoskeleton. Cofilin enhances actin polymerization via its actin-severing activity, and as a long-lasting effect, cofilin generates novel actin monomers through F-actin depolymerization. L-plastin stabilizes acin filament structures by means of its actin-bundling activity.
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Actin remodeling
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The actin cytoskeletal network plays a regulatory role in receptor-mediated signal-transducing events. Recently, we have shown that the small actin-depolymerizing protein cofilin represents a component of a co-stimulatory signaling pathway in human T cells. Cofilin is dephosphorylated on phosphoserine residues following co-stimulation via accessory receptors such as CD2, CD4, CD8 or CD28, but not in response to TCR engagement alone. Here we demonstrate that accessory receptor triggering induces the transient association of cofilin with the actin cytoskeleton. Only the dephosphorylated form of cofilin binds to cytoskeletal actin in vivo. The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 block dephosphorylation of cofilin and its association with the actin cytoskeleton. These results suggest that cofilin provides an as yet missing link between functionally crucial T cell surface receptors and rearrangements of the actin cytoskeleton.
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Cell migration plays a vital role in both health and disease. It is driven by reorganization of the actin cytoskeleton, which is regulated by actin-binding proteins cofilin and profilin. Stress-inducible phosphoprotein 1 (STIP1) is a well-described co-chaperone of the Hsp90 chaperone system, and our findings identify a potential regulatory role of STIP1 in actin dynamics. We show that STIP1 can be isolated in complex with actin and Hsp90 from HEK293T cells and directly interacts with actin in vitro via the C-terminal TPR2AB-DP2 domain of STIP1, potentially due to a region spanning two putative actin-binding motifs. We found that STIP1 could stimulate the in vitro ATPase activity of actin, suggesting a potential role in the modulation of F-actin formation. Interestingly, while STIP1 depletion in HEK293T cells had no major effect on total actin levels, it led to increased nuclear accumulation of actin, disorganization of F-actin structures, and an increase and decrease in cofilin and profilin levels, respectively. This study suggests that STIP1 regulates the cytoskeleton by interacting with actin, or via regulating the ratio of proteins known to affect actin dynamics.
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Rapid turnover of actin structures is required for dynamic remodeling of the cytoskeleton and cell morphogenesis, but the mechanisms driving actin disassembly are poorly defined. Cofilin plays a central role in promoting actin turnover by severing/depolymerizing filaments. Here, we analyze the in vivo function of a ubiquitous actin-interacting protein, Aip1, suggested to work with cofilin. We provide the first demonstration that Aip1 promotes actin turnover in living cells. Further, we reveal an unanticipated role for Aip1 and cofilin in promoting rapid turnover of yeast actin cables, dynamic structures that are decorated and stabilized by tropomyosin. Through systematic mutagenesis of Aip1 surfaces, we identify two well-separated F-actin-binding sites, one of which contributes to actin filament binding and disassembly specifically in the presence of cofilin. We also observe a close correlation between mutations disrupting capping of severed filaments in vitro and reducing rates of actin turnover in vivo. We propose a model for balanced regulation of actin cable turnover, in which Aip1 and cofilin function together to "prune" tropomyosin-decorated cables along their lengths. Consistent with this model, deletion of AIP1 rescues the temperature-sensitive growth and loss of actin cable defects of tpm1Delta mutants.
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Abstract The cover image of this issue consists of a confocal microscopic FRET image showing immunological synapse formation in Jurkat T cells, and is taken from Roszik et al. ( pp . 1288–1297). In this article, the authors characterize TCR‐ζ, a heterodimer of TCR‐α and β chains each coupled to complete human CD3ζ, in gene‐engineered T cells and assess whether this receptor is able to interact with surface molecules and drive correct synapse formation in Jurkat T cells. The authors notably demonstrate that TCR‐ζ is able to induce synapse formation upon antigen recognition, and that synapse formation induced by TCR‐ζ is independent of TCR‐CD3.
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T lymphocyte activation by specific antigen requires prolonged TCR occupancy and sustained signaling. This is accomplished by the formation of a specialized signaling domain, the immunological synapse, at the T cell–antigen-presenting cell contact site. Surface receptors and signaling components are progressively recruited into this domain where they are organized in defined three-dimensional structures. To better understand how TCR are supplied to the signaling domain during the activation process, we measured (using confocal microscopy and photo-bleaching recovery techniques) lateral mobility of GFP-tagged TCR on living Jurkat cell surface. We show that: (i) surface-expressed TCR exhibit an intrinsic, actin cytoskeleton-independent, lateral mobility which allows them to passively diffuse over the entire T cell surface within ~60 min and (ii) non-stimulated TCR rapidly enter the signaling domain. Our results indicate that TCR lateral mobility per se is sufficient to ensure TCR supply to the immunological synapse in the course of sustained T cell activation.
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The actin cytoskeletal network plays a regulatory role in receptor-mediated signal-transducing events. Recently, we have shown that the small actin-depolymerizing protein cofilin represents a component of a co-stimulatory signaling pathway in human T cells. Cofilin is dephosphorylated on phosphoserine residues following co-stimulation via accessory receptors such as CD2, CD4, CD8 or CD28, but not in response to TCR engagement alone. Here we demonstrate that accessory receptor triggering induces the transient association of cofilin with the actin cytoskeleton. Only the dephosphorylated form of cofilin binds to cytoskeletal actin in vivo. The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 block dephosphorylation of cofilin and its association with the actin cytoskeleton. These results suggest that cofilin provides an as yet missing link between functionally crucial T cell surface receptors and rearrangements of the actin cytoskeleton.
Cofilin
Actin remodeling
Profilin
MDia1
Actin-binding protein
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Citations (78)