Oxidation of Cofilin Mediates T Cell Hyporesponsiveness under Oxidative Stress Conditions

Institute for Immunology, University of Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg, Germany.
Immunity (Impact Factor: 21.56). 10/2008; 29(3):404-13. DOI: 10.1016/j.immuni.2008.06.016
Source: PubMed


Oxidative stress leads to impaired T cell activation. A central integrator of T cell activation is the actin-remodelling protein cofilin. Cofilin is activated through dephosphorylation at Ser3. Activated cofilin enables actin dynamics through severing and depolymerization of F-actin. Binding of cofilin to actin is required for formation of the immune synapse and T cell activation. Here, we showed that oxidatively stressed human T cells were impaired in chemotaxis- and costimulation-induced F-actin modulation. Although cofilin was dephosphorylated, steady-state F-actin levels increased under oxidative stress conditions. Mass spectrometry revealed that cofilin itself was a target for oxidation. Cofilin oxidation induced formation of an intramolecular disulfide bridge and loss of its Ser3 phosphorylation. Importantly, dephosphorylated oxidized cofilin, although still able to bind to F-actin, did not mediate F-actin depolymerization. Impairing actin dynamics through oxidation of cofilin provides a molecular explanation for the T cell hyporesponsiveness caused by oxidative stress.

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Available from: Henning Kirchgessner, Oct 29, 2015
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    • "Several mechanisms have been reported to inhibit cofilin activity (Figure 2A), including phosphorylation at position 3 (Ser3; Agnew et al., 1995; Moriyama et al., 1996), binding of PtdIns(4,5)P 2 (Frantz et al., 2008), tyrosine phosphorylation at position 68 (Tyr68; Yoo et al., 2010), oxidation (Klemke et al., 2008; Pfannstiel et al., 2001) and decreased intracellular pH (Bernstein et al., 2000; Yonezawa et al., 1985). Besides, cofilin F-actin depolymerizing activity can be enhanced with actin-interacting protein-1 (AIP1) and cyclaseassociated protein (CAP; Brieher, 2013; Ono, 2013). "
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    ABSTRACT: Actin-depolymerizing factor (ADF)/cofilin proteins are key players in controlling the temporal and spatial extent of actin dynamics, which is crucial for mediating host-pathogen interactions. Pathogenic microbes have evolved molecular mechanisms to manipulate cofilin activity to subvert the actin cytoskeletal system in host cells, promoting their internalization into the target cells, modifying the replication niche and facilitating their intracellular and intercellular dissemination. The study of how these pathogens exploit cofilin pathways is crucial for understanding infectious disease and providing potential targets for drug therapies.
    Critical Reviews in Microbiology 04/2015; DOI:10.3109/1040841X.2015.1010139 · 6.02 Impact Factor
    • "Cofilin also contains four cysteine residues that can be potentially oxidized (Samstag et al., 2013). Indeed recent data have shown that C139 is sulfonylated , whereas C39 and C80 are possibly involved in the formation of an intramolecular disulfide bridge under oxidative stress (Klemke et al., 2008; Samstag et al., 2013). Cofilin oxidation parallels with the loss of S3 phosphorylation , thus impairing its ability to remodel actin and ultimately leading to T-cell hyporesponsiveness. "
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    ABSTRACT: T-cell receptor (TCR) triggering by antigens activates a sophisticated intracellular signaling network leading to transcriptional activation, proliferation and differentiation of T cells. These events ultimately culminate in adaptive immune responses. Over the past years, it has become evident that reactive oxygen species (ROS) play an important role in T-cell activation. It is now clear that ROS are involved in the regulation of T-cell mediated physiological and pathological processes. Upon TCR triggering, T cells produce oxidants which originate from different cellular sources. In addition, within inflamed tissues, T cells are exposed to exocrine ROS produced by activated phagocytes or other ROS-producing cells. Oxidative modifications can have different effects on T-cell function. Indeed, they can stimulate T-cell activation but they can be also detrimental. These opposite effects of oxidation likely depend on different factors such as ROS concentration and source and also on the differentiation status of the T cells. Despite the well-stablished fact that ROS represent important modulators of T-cell activation, the precise molecular mechanisms of their action are far from being elucidated. Here, we summarize the present knowledge on redox regulation of T-cell function with a particular emphasis on the redox regulation of TCR signaling.
    Biological Chemistry 03/2015; 396(5). DOI:10.1515/hsz-2014-0312 · 3.27 Impact Factor
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    • "On the other hand, ROS, particularly those produced by a NOX, have been implicated in the regulation of cytoskeletal remodeling [42]. For example, the oxidation of the actin binding protein cofilin stimulates apoptosis [43] and impairs cytoskeletal function in T cells [44]. Also, a redox imbalance modifies the actin cytoskeleton of cortical astrocytes [45] and H2O2 alters astrocyte cytoskeleton through the activation of the p38 MAPK pathway [46]. "
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    ABSTRACT: Cell death implies morphological changes that may contribute to the progression of this process. In astrocytes, the mechanisms involving the cytoskeletal changes during cell death are not well explored. Although NADPH oxidase (NOX) has been described as being a critical factor in the production of ROS, not much information is available about the participation of NOX-derived ROS in the cell death of astrocytes and their role in the alterations of the cytoskeleton during the death of astrocytes. In this study, we have evaluated the participation of ROS in the death of cultured cerebellar astrocytes using staurosporine (St) as death inductor. We found that astrocytes express NOX1, NOX2, and NOX4. Also, St induced an early ROS production and NOX activation that participate in the death of astrocytes. These findings suggest that ROS produced by St is generated through NOX1 and NOX4. Finally, we showed that the reorganization of tubulin and actin induced by St is ROS independent and that St did not change the level of expression of these cytoskeletal proteins. We conclude that ROS produced by a NOX is required for cell death in astrocytes, but not for the morphological alterations induced by St.
    Oxidative medicine and cellular longevity 08/2014; 2014:678371. DOI:10.1155/2014/678371 · 3.36 Impact Factor
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