S-Glutathionylation Impairs Signal Transducer and Activator of Transcription 3 Activation and Signaling
Autor: | Sutapa Kole, Patricia Precht, Michel Bernier, Yi Xie, Michael J. Pazin |
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Rok vydání: | 2008 |
Předmět: |
STAT3 Transcription Factor
Pyrrolidines Diamines Biology Transfection Antioxidants Article chemistry.chemical_compound Endocrinology Pyrrolidine dithiocarbamate Thiocarbamates Humans Cysteine Phosphorylation S-Glutathionylation STAT3 Cells Cultured Glutaredoxins Interleukin-6 Tyrosine phosphorylation Glutathione Janus Kinase 2 Oxidants Biochemistry chemistry biology.protein Signal transduction Protein Processing Post-Translational Signal Transduction |
Zdroj: | Endocrinology. 150:1122-1131 |
ISSN: | 1945-7170 0013-7227 |
Popis: | S-glutathionylation is a physiological, reversible protein modification of cysteine residues with glutathione in response to mild oxidative stress. Because the key cell growth regulator signal transducer and activator of transcription (STAT) 3 is particularly susceptible to redox regulation, we hypothesized that oxidative modification of cysteine residues of STAT3 by S-glutathionylation may occur. Herein, we show that the cysteine residues of STAT3 are modified by a thiol-alkylating agent and are the targets of S-glutathionylation. STAT3 protein thiol reactivity was reversibly attenuated with concomitant increase in the S-glutathionylation of STAT3 upon treatment of human HepG2 hepatoma cells with pyrrolidine dithiocarbamate, glutathione disulfide, or diamide. Under these conditions there was a marked reduction in IL-6-dependent STAT3 signaling, including decreased STAT3 tyrosine phosphorylation, loss in nuclear accumulation of STAT3, and impaired expression of target genes, such as fibrinogen-γ. In a cell-free system, diamide induced glutathionylation of STAT3, which was decreased upon addition of glutaredoxin (GRX)-1, a deglutathionylation enzyme, or the reducing agent, dithiothreitol. Glutathionylated STAT3 was a poor Janus protein tyrosine kinase 2 substrate in vitro, and it exhibited low DNA-binding activity. Cellular GRX-1 activity was inhibited by diamide and pyrrolidine dithiocarbamate treatment; however, ectopic expression of GRX-1 was accompanied by a modest increase in phosphorylation, nuclear translocation, and DNA-binding ability of STAT3 in response to IL-6. These results are the first to show S-glutathionylation of STAT3, a modification that may exert regulatory function in STAT3 signaling.Reversible S-glutathionylation of STAT3 regulates its activity as transcription factor. |
Databáze: | OpenAIRE |
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