title: Nuclear glutaredoxin 3 is critical for protection against oxidative stress-induced cell death.
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.
authors.affiliation: USDA/ARS Children׳s Nutrition Research Center, Department of Pediatrics, Houston, TX 77030, USA.
authors.forename: Khanh
authors.initials: K
authors.lastname: Pham
authors.affiliation: Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Rituraj
authors.initials: R
authors.lastname: Pal
authors.affiliation: Department of Surgery and Department of Obstetrics and Gynecology, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Ministry of Education Key Laboratory of Protein Science, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Liu
authors.affiliation: USDA/ARS Children׳s Nutrition Research Center, Department of Pediatrics, Houston, TX 77030, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Yu
authors.affiliation: Radiation Oncology and Biochemical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Shiao
authors.affiliation: Ministry of Education Key Laboratory of Protein Science, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Xinquan
authors.initials: X
authors.lastname: Wang
authors.affiliation: USDA/ARS Children׳s Nutrition Research Center, Department of Pediatrics, Houston, TX 77030, USA.
authors.forename: E
authors.initials: E
authors.lastname: O'Brian Smith
authors.affiliation: 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.
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Cui
authors.affiliation: Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: George G
authors.initials: GG
authors.lastname: Rodney
authors.affiliation: USDA/ARS Children׳s Nutrition Research Center, Department of Pediatrics, Houston, TX 77030, USA. Electronic address: ncheng@bcm.edu.
authors.forename: Ninghui
authors.initials: N
authors.lastname: Cheng
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D006801:Humans; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C404105:GLRX3 protein, human; D017382:Reactive Oxygen Species
keywords: Cell death; Free radicals; Glutaredoxin; Oxidative stress; Redox homeostasis