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Free Radic Biol Med. 2015 Sep;86:1-15. doi: 10.1016/j.freeradbiomed.2015.04.008. Epub 2015 Apr 14.

L-Plastin S-glutathionylation promotes reduced binding to β-actin and affects neutrophil functions.

Author information

1
Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India.
2
Division of Experimental Hematology and Cancer Biology, Cincinnati Children׳s Research Foundation, Cincinnati, OH 45229, USA.
3
King George׳s Medical University, Lucknow, India.
4
Centre for Cellular and Molecular Platforms, National Centre for Biological Sciences (NCBS-TIFR), Bangalore, India.
5
Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM), Campus Universidad Autónoma, Nicolás, Cabrera 1, E-28049, Madrid, Spain.
6
Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India. Electronic address: madhu_dikshit@cdri.res.in.

Abstract

Posttranslational modifications (PTMs) of cytoskeleton proteins due to oxidative stress associated with several pathological conditions often lead to alterations in cell function. The current study evaluates the effect of nitric oxide (DETA-NO)-induced oxidative stress-related S-glutathionylation of cytoskeleton proteins in human PMNs. By using in vitro and genetic approaches, we showed that S-glutathionylation of L-plastin (LPL) and β-actin promotes reduced chemotaxis, polarization, bactericidal activity, and phagocytosis. We identified Cys-206, Cys-283, and Cys-460as S-thiolated residues in the β-actin-binding domain of LPL, where cys-460 had the maximum score. Site-directed mutagenesis of LPL Cys-460 further confirmed the role in the redox regulation of LPL. S-Thiolation diminished binding as well as the bundling activity of LPL. The presence of S-thiolated LPL was detected in neutrophils from both diabetic patients and db/db mice with impaired PMN functions. Thus, enhanced nitroxidative stress may results in LPL S-glutathionylation leading to impaired chemotaxis, polarization, and bactericidal activity of human PMNs, providing a mechanistic basis for their impaired functions in diabetes mellitus.

KEYWORDS:

Bactericidal activity; Chemotaxis; Diabetes; Nitric oxide; Oxidative stress; Phagocytosis; Polarization; Posttranslational modifications

[Indexed for MEDLINE]

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