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Cell Rep. 2017 Jul 5;20(1):224-235. doi: 10.1016/j.celrep.2017.05.070.

Positive Regulation of Interleukin-1β Bioactivity by Physiological ROS-Mediated Cysteine S-Glutathionylation.

Author information

1
Department of Pathology and Pathophysiology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China; Department of Pathology, Harvard Medical School, Boston, MA 02115, USA; Department of Lab Medicine, Children's Hospital Boston, Dana-Farber/Harvard Cancer Center, Boston, MA 02115, USA. Electronic address: zhangxue@zju.edu.cn.
2
The State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China.
3
Department of Pathology, Harvard Medical School, Boston, MA 02115, USA; Department of Lab Medicine, Children's Hospital Boston, Dana-Farber/Harvard Cancer Center, Boston, MA 02115, USA.
4
Hematopathology, Flow Cytometry, Hematology, and Blood Bank Labs, VA Boston Healthcare System, West Roxbury, MA 02132, USA; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 01605, USA.
5
Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA.
6
Department of Pathology and Pathophysiology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China; Department of Pathology, Harvard Medical School, Boston, MA 02115, USA; Department of Lab Medicine, Children's Hospital Boston, Dana-Farber/Harvard Cancer Center, Boston, MA 02115, USA.
7
Institute of Environmental Health Sciences and Department of Biochemistry and Molecular Biology, Wayne State University, Detroit, MI 48201, USA.
8
Mass Spectrometry Unit, Waters Corporation, Milford, MA 01757, USA.
9
Department of Chemistry, Brandeis University, 415 South Street MS015, Waltham, MA 02454, USA.
10
Department of Pathology, Harvard Medical School, Boston, MA 02115, USA; Department of Lab Medicine, Children's Hospital Boston, Dana-Farber/Harvard Cancer Center, Boston, MA 02115, USA. Electronic address: hongbo.luo@childrens.harvard.edu.

Abstract

Reactive oxygen species (ROS)-induced cysteine S-glutathionylation is an important posttranslational modification (PTM) that controls a wide range of intracellular protein activities. However, whether physiological ROS can modulate the function of extracellular components via S-glutathionylation is unknown. Using a screening approach, we identified ROS-mediated cysteine S-glutathionylation on several extracellular cytokines. Glutathionylation of the highly conserved Cys-188 in IL-1β positively regulates its bioactivity by preventing its ROS-induced irreversible oxidation, including sulfinic acid and sulfonic acid formation. We show this mechanism protects IL-1β from deactivation by ROS in an in vivo system of irradiation-induced bone marrow (BM) injury. Glutaredoxin 1 (Grx1), an enzyme that catalyzes deglutathionylation, was present and active in the extracellular space in serum and the BM, physiologically regulating IL-1β glutathionylation and bioactivity. Collectively, we identify cysteine S-glutathionylation as a cytokine regulatory mechanism that could be a therapeutic target in the treatment of various infectious and inflammatory diseases.

KEYWORDS:

cysteine S-glutathionylation; cytokines; infection and inflammation; interleukin-1; oxidation; posttranslational modification; reactive oxygen species

PMID:
28683316
PMCID:
PMC5758045
DOI:
10.1016/j.celrep.2017.05.070
[Indexed for MEDLINE]
Free PMC Article

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