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

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 act...

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Main Authors: Schulte, Bianca (Author) , John, Isabel (Author) , Simon, Bernd (Author) , Brockmann, Christoph (Author) , Oelmeier, Stefan A. (Author) , Jahraus, Beate (Author) , Kirchgessner, Henning (Author) , Riplinger, Selina (Author) , Carlomagno, Teresa (Author) , Wabnitz, Guido H. (Author) , Samstag, Yvonne (Author)
Format: Article (Journal)
Language:English
Published: 2013
In: The journal of biological chemistry
Year: 2013, Volume: 288, Issue: 41, Pages: 29430-29439
ISSN:1083-351X
DOI:10.1074/jbc.M113.479766
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1074/jbc.M113.479766
Verlag, lizenzpflichtig, Volltext: https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)48764-2
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Author Notes: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

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245 1 2 |a A reducing milieu renders cofilin insensitive to phosphatidylinositol 4,5-bisphosphate (PIP2) inhibition  |c 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 
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520 |a 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. 
650 4 |a Actin Depolymerizing Factors 
650 4 |a Actins 
650 4 |a Blotting, Western 
650 4 |a Cell Line, Tumor 
650 4 |a Cell Membrane 
650 4 |a Cells, Cultured 
650 4 |a Cofilin 
650 4 |a Cysteine 
650 4 |a Humans 
650 4 |a Magnetic Resonance Spectroscopy 
650 4 |a Models, Molecular 
650 4 |a Molecular Dynamics Simulation 
650 4 |a Mutation 
650 4 |a Oxidation-Reduction 
650 4 |a Phosphatidylinositol 4,5-Diphosphate 
650 4 |a Phosphatidylinositol Signaling 
650 4 |a Phosphorylation 
650 4 |a Polymerization 
650 4 |a Protein Binding 
650 4 |a Protein Conformation 
650 4 |a Protein Structure, Tertiary 
650 4 |a Redox Regulation 
650 4 |a T Cell 
650 4 |a T-Lymphocytes 
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