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Free Radic Biol Med. 2015 Aug;85:197-206. doi: 10.1016/j.freeradbiomed.2015.05.003. Epub 2015 May 11.

Nuclear glutaredoxin 3 is critical for protection against oxidative stress-induced cell death.

Author information

1
USDA/ARS Children׳s Nutrition Research Center, Department of Pediatrics, Houston, TX 77030, USA.
2
Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
3
Department of Surgery and Department of Obstetrics and Gynecology, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA.
4
Ministry of Education Key Laboratory of Protein Science, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
5
Radiation Oncology and Biochemical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA.
6
Department of Surgery and Department of Obstetrics and Gynecology, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address: Xiaojiang.Cui@cshs.org.
7
USDA/ARS Children׳s Nutrition Research Center, Department of Pediatrics, Houston, TX 77030, USA. Electronic address: ncheng@bcm.edu.

Abstract

Mammalian glutaredoxin 3 (Grx3) has been shown to be critical in maintaining redox homeostasis and regulating cell survival pathways in cancer cells. However, the regulation of Grx3 is not fully understood. In the present study, we investigate the subcellular localization of Grx3 under normal growth and oxidative stress conditions. Both fluorescence imaging of Grx3-RFP fusion and Western blot analysis of cellular fractionation indicate that Grx3 is predominantly localized in the cytoplasm under normal growth conditions, whereas under oxidizing conditions, Grx3 is translocated into and accumulated in the nucleus. Grx3 nuclear accumulation was reversible in a redox-dependent fashion. Further analysis indicates that neither the N-terminal Trx-like domain nor the two catalytic cysteine residues in the active CGFS motif of Grx3 are involved in its nuclear translocation. Decreased levels of Grx3 render cells susceptible to cellular oxidative stress, whereas overexpression of nuclear-targeted Grx3 is sufficient to suppress cells' sensitivity to oxidant treatments and reduce reactive oxygen species production. These findings provide novel insights into the regulation of Grx3, which is crucial for cell survival against environmental insults.

KEYWORDS:

Cell death; Free radicals; Glutaredoxin; Oxidative stress; Redox homeostasis

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