Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 86, Issue -, Pages 1-15Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2015.04.008
Keywords
Chemotaxis; Polarization; Phagocytosis; Bactericidal activity; Nitric oxide; Diabetes; Oxidative stress; Posttranslational modifications
Funding
- Department of Biotechnology-INDIGO
- CSIR network [BSC0102]
- New Indigo Programme [PIM 2010 ENI-00631]
- Ministerio de Economia y Competitividad (MINECO), SAF [2012-31388]
- Council of Scientific and Industrial Research, India
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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)-incluced oxidative stress-related S-glutathionylation of cytoskeleton proteins in human PMNs. By using in vitro and genetic approaches, we showed that 5-glutathionylation of L-plastin (LPL) and beta-actin promotes reduced chemotaxis, polarization, bactericidal activity, and phagocytosis. We identified Cys-206, Cys-283, and Cys-460 as S-thiolated residues in the beta-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. (C) 2015 Elsevier Inc. All rights reserved.
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