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S-Glutathionylation Impairs Signal Transducer and Activator of Transcription 3 Activation and Signaling
Open accessAbstract
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.
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“STAT3 itself can be subject to direct modification by oxidative stress, as 9 of the 14 cysteine residues within STAT3 have been reported to be redox sensitive.”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Xie et al., 2009
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“These modifications affect the transcriptional activity of STAT3 through inhibiting Y705 phosphorylation and/or DNA binding, as well as inducing formation of higher order complexes and interfering with the function of the TAD (Li and Shaw, 2004; Xie et al., 2009; Li et al., 2010a; Kurdi et al., 2012; Butturini et al., 2014; Sobotta et al., 2015).”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Xie et al., 2009
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“thiol-targeting agents also inhibited IL-6–induced STAT3 activation by S-glutathionylation in HepG2 cells (Xie et al., 2009), human endothelial cells, neonatal rat cardiomyocytes, and adult mouse cardiac myocytes (Zgheib et al., 2012)”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Xie et al., 2009
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Cites
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Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase
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The role of IL-6 and STAT3 in inflammation and cancer
Hodge, D. R., Hurt, E. M., & Farrar, W. L. (2005) · European Journal of Cancer · doi:10.1016/j.ejca.2005.08.016 · Cited by 966
The Biotin Switch Method for the Detection of S -Nitrosylated Proteins
Jaffrey, S. R., & Snyder, S. H. (2001) · Science Signaling · doi:10.1126/stke.2001.86.pl1 · Cited by 855
Regulation of protein function by S‐glutathiolation in response to oxidative and nitrosative stress
Klatt, P., & Lamas, S. (2000) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.2000.01601.x · Cited by 757
Siddiquee, K., Zhang, S., Guida, W. C., Blaskovich, M. A., Greedy, B. M., Lawrence, H. R., Yip, M. L. R., Jove, R., McLaughlin, M. M., Lawrence, N. J., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0609757104 · Cited by 741
Mechanisms of reversible protein glutathionylation in redox signaling and oxidative stress
Gallogly, M. M., & Mieyal, J. J. (2007) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2007.06.003 · Cited by 476
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“The transactivation domain (TAD) plays a role in the recruitment of coactivators with histone acetyltransferase activity to facilitate transcriptional activation.”
BackgroundInfluentialSTAT proteins in cancer: orchestration of metabolism
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Metadata
- Authors
- Xie, Y., Kole, S., Precht, P., Pazin, M. J., & Bernier, M.
- Affiliations
- National Institutes of Health (US)
- MedStar Health Research Institute (US)
- Corresponding author
- Bernier, Michel
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2008-11-06
- Volume
- 150
- Issue
- 3
- Pages
- 1122-1131
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC2654735
- OpenAlex
- W1996740511
- Cited by
- 126
- References
- 61
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 4 · 2022: 4 · 2021: 9 · 2020: 10 · 2019: 8 · 2018: 4 · 2017: 11 · 2016: 7 · 2015: 9 · 2014: 13 · 2013: 12 · 2012: 5
- FWCI
- 2.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Endocrinology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (ZIAAG000378)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Keywords
- S-glutathionylation, STAT3, cysteine oxidation, glutaredoxin 1, IL-6 signaling, STAT3 tyrosine phosphorylation, nuclear translocation, DNA-binding activity, oxidative stress, diamide, pyrrolidine dithiocarbamate, protein thiol modification
- MeSH terms
- Antioxidants, Cells, Cultured, Cysteine, Diamines, Glutathione, Humans, Phosphorylation, Protein Processing, Post-Translational, Pyrrolidines, Thiocarbamates, Transfection, Signal Transduction, Interleukin-6, Oxidants, STAT3 Transcription Factor, Janus Kinase 2, Glutaredoxins
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