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: | , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2013
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| 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 |
| Summary: | 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. |
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| Item Description: | Gesehen am 28.06.2021 |
| Physical Description: | Online Resource |
| ISSN: | 1083-351X |
| DOI: | 10.1074/jbc.M113.479766 |