A Reducing Milieu Renders Cofilin Insensitive to Phosphatidylinositol 4,5-Bisphosphate (PIP2) Inhibition

Schulte, Bianca; John, Isabel; Simon, Bernd; Brockmann, Christoph; Oelmeier, Stefan A.; Jahraus, Beate; Kirchgessner, h.c. mult. M.; Riplinger, Selina M; Carlomagno, Teresa; Wabnitz, Guido H.; Samstag, Yvonne

doi:10.1074/jbc.m113.479766

Cited by 14 publications

(17 citation statements)

References 35 publications

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“…Consistent with this, instantaneous chromophore-assisted laser inactivation revealed that active cofilin normally promotes lamellipodial F-actin turnover [ 24 ]. An additional potential contributing factor is that oxidized cofilin at plasma membranes is likely to be inactivated by membrane lipid association, unlike reduced cofilin that was shown to be insensitive to phosphatidylinositol 4,5-bisphosphate (PIP 2 )-induced inhibition [ 25 ]. Furthermore, cofilin oxidation might reduce competition with myosin II for F-actin binding, thereby enabling development of actin-myosin cortical tension that contributes to cell motility independent of F-actin turnover [ 26 ].…”

Section: Resultsmentioning

confidence: 99%

Polarized Cell Motility Induces Hydrogen Peroxide to Inhibit Cofilin via Cysteine Oxidation

et al. 2015

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SummaryMesenchymal cell motility is driven by polarized actin polymerization [1]. Signals at the leading edge recruit actin polymerization machinery to promote membrane protrusion, while matrix adhesion generates tractive force to propel forward movement. To work effectively, cell motility is regulated by a complex network of signaling events that affect protein activity and localization. H2O2 has an important role as a diffusible second messenger [2], and mediates its effects through oxidation of cysteine thiols. One cell activity influenced by H2O2 is motility [3]. However, a lack of sensitive and H2O2-specific probes for measurements in live cells has not allowed for direct observation of H2O2 accumulation in migrating cells or protrusions. In addition, the identities of proteins oxidized by H2O2 that contribute to actin dynamics and cell motility have not been characterized. We now show, as determined by fluorescence lifetime imaging microscopy, that motile cells generate H2O2 at membranes and cell protrusions and that H2O2 inhibits cofilin activity through oxidation of cysteines 139 (C139) and 147 (C147). Molecular modeling suggests that C139 oxidation would sterically hinder actin association, while the increased negative charge of oxidized C147 would lead to electrostatic repulsion of the opposite negatively charged surface. Expression of oxidation-resistant cofilin impairs cell spreading, adhesion, and directional migration. These findings indicate that H2O2 production contributes to polarized cell motility through localized cofilin inhibition and that there are additional proteins oxidized during cell migration that might have similar roles.

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Section: Resultsmentioning

confidence: 99%

Polarized Cell Motility Induces Hydrogen Peroxide to Inhibit Cofilin via Cysteine Oxidation

et al. 2015

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“…Phosphorylation and thereby inactivation of cofilin is mediated by LimKinase (LimK) and testis‐specific kinases (TES kinases) (reviewed in ). The involvement of PP1 in cofilin regulation could recently be confirmed by knockdown of PP1 in untransformed human T cells . The contribution of the other enzymes to the regulation of cofilin in untransformed T cells remains to be analyzed in detail.…”

Section: Cofilin Activation Induced By T‐cell Costimulationmentioning

confidence: 94%

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

Samstag

John

Wabnitz

2013

Immunological Reviews

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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.

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“…Upon specific stimuli, including a so far unknown cellular reductase, the reduction of cofilin prevents the inhibition by PIP 2 , resulting in increased actin dynamics, e.g. in the immune synapse of untransformed T cells [106]. The Cys39-Cys147 intermolecular disulfide was confirmed in vivo and was shown to be important for the cofilin-actin rod formation in neurons [108].…”

Section: Redox Regulation Of Cofilin Activitymentioning

confidence: 95%

“…Following protein expression cofilin-1 contains at least one disulfide bridge in vivo, possibly involving Cys39 and Cys80, that is susceptible to reduction [106]. The authors furthermore claimed, that the surfaces Cys139 and Cys147 are most likely essential for protein oligomerization, a process that has been described for cofilin-1 before [107][108][109].…”

Section: Redox Regulation Of Cofilin Activitymentioning

confidence: 95%

“…The authors furthermore claimed, that the surfaces Cys139 and Cys147 are most likely essential for protein oligomerization, a process that has been described for cofilin-1 before [107][108][109]. Mutating these Cys residues to Ala renders the protein more stable than the WT and prevents oligomerization and protein aggregation [106]. A different study indicated Cys39 and Cys147 to be involved in the formation of intermolecular disulfides and oligomers that constitute different redox states of the protein with distinct biological functions.…”

Section: Redox Regulation Of Cofilin Activitymentioning

confidence: 96%

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Redox regulation of cytoskeletal dynamics during differentiation and de-differentiation

Gellert

Hanschmann

Lepka

et al. 2015

Biochimica et Biophysica Acta (BBA) - General Subjects

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A Reducing Milieu Renders Cofilin Insensitive to Phosphatidylinositol 4,5-Bisphosphate (PIP2) Inhibition

Cited by 14 publications

References 35 publications

Polarized Cell Motility Induces Hydrogen Peroxide to Inhibit Cofilin via Cysteine Oxidation

Polarized Cell Motility Induces Hydrogen Peroxide to Inhibit Cofilin via Cysteine Oxidation

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

Redox regulation of cytoskeletal dynamics during differentiation and de-differentiation

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