A reducing milieu renders cofilin insensitive to phosphatidylinositol 4,5-bisphosphate (PIP2) inhibition

• Verfasst von: Schulte, Bianca [VerfasserIn]
• Verfasst von: John, Isabel [VerfasserIn]
• Verfasst von: Simon, Bernd [VerfasserIn]
• Verfasst von: Brockmann, Christoph [VerfasserIn]
• Verfasst von: Oelmeier, Stefan A. [VerfasserIn]
• Verfasst von: Jahraus, Beate [VerfasserIn]
• Verfasst von: Kirchgessner, Henning [VerfasserIn]
• Verfasst von: Riplinger, Selina [VerfasserIn]
• Verfasst von: Carlomagno, Teresa [VerfasserIn]
• Verfasst von: Wabnitz, Guido H. [VerfasserIn]
• Verfasst von: Samstag, Yvonne [VerfasserIn]
• Titel: A reducing milieu renders cofilin insensitive to phosphatidylinositol 4,5-bisphosphate (PIP2) inhibition
• Verf.angabe: Bianca Schulte, Isabel John, Bernd Simon, Christoph Brockmann, Stefan A. Oelmeier, Beate Jahraus, Henning Kirchgessner, Selina Riplinger, Teresa Carlomagno, Guido H. Wabnitz and Yvonne Samstag
• Jahr: 2013
• Umfang: 10 S.
• Teil: volume:288
• Teil: year:2013
• Teil: number:41
• Teil: pages:29430-29439
• Teil: extent:10
• Fussnoten: Gesehen am 28.06.2021
• Titel Quelle: Enthalten in: The journal of biological chemistry
• Ort Quelle: Bethesda, Md. : ASBMB Publications, 1905
• Jahr Quelle: 2013
• Band/Heft Quelle: 288(2013), 41, Seite 29430-29439
• ISSN Quelle: 1083-351X
• DOI: doi:10.1074/jbc.M113.479766
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Actin Depolymerizing Factors
• Sach-SW: Actins
• Sach-SW: Blotting, Western
• Sach-SW: Cell Line, Tumor
• Sach-SW: Cell Membrane
• Sach-SW: Cells, Cultured
• Sach-SW: Cofilin
• Sach-SW: Cysteine
• Sach-SW: Humans
• Sach-SW: Magnetic Resonance Spectroscopy
• Sach-SW: Models, Molecular
• Sach-SW: Molecular Dynamics Simulation
• Sach-SW: Mutation
• Sach-SW: Oxidation-Reduction
• Sach-SW: Phosphatidylinositol 4,5-Diphosphate
• Sach-SW: Phosphatidylinositol Signaling
• Sach-SW: Phosphorylation
• Sach-SW: Polymerization
• Sach-SW: Protein Binding
• Sach-SW: Protein Conformation
• Sach-SW: Protein Structure, Tertiary
• Sach-SW: Redox Regulation
• Sach-SW: T Cell
• Sach-SW: T-Lymphocytes
• K10plus-PPN: 1761321447

Abstract

Oxidative stress can lead to T cell hyporesponsiveness. A reducing micromilieu (e.g. provided by dendritic cells) can rescue T cells from such oxidant-induced dysfunction. However, the reducing effects on proteins leading to restored T cell activation remained unknown. One key molecule of T cell activation is the actin-remodeling protein cofilin, which is dephosphorylated on serine 3 upon T cell costimulation and has an essential role in formation of mature immune synapses between T cells and antigen-presenting cells. Cofilin is spatiotemporally regulated; at the plasma membrane, it can be inhibited by phosphatidylinositol 4,5-bisphosphate (PIP2). Here, we show by NMR spectroscopy that a reducing milieu led to structural changes in the cofilin molecule predominantly located on the protein surface. They overlapped with the PIP2- but not actin-binding sites. Accordingly, reduction of cofilin had no effect on F-actin binding and depolymerization and did not influence the cofilin phosphorylation state. However, it did prevent inhibition of cofilin activity through PIP2. Therefore, a reducing milieu may generate an additional pool of active cofilin at the plasma membrane. Consistently, in-flow microscopy revealed increased actin dynamics in the immune synapse of untransformed human T cells under reducing conditions. Altogether, we introduce a novel mechanism of redox regulation: reduction of the actin-remodeling protein cofilin renders it insensitive to PIP2 inhibition, resulting in enhanced actin dynamics.