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Redox regulatory and anti-apoptotic functions of thioredoxin depend on S-nitrosylation at cysteine 69

Nature Cell Biology volume 4, pages 743–749 (2002)Cite this article

An Erratum to this article was published on 01 March 2003

Abstract

Thioredoxin 1 (Trx) is a known redox regulator that is implicated in the redox control of cell growth and apoptosis inhibition. Here we show that Trx is essential for maintaining the content of S-nitrosylated molecules in endothelial cells. Trx itself is S-nitrosylated at cysteine 69 under basal conditions, and this S-nitrosylation is required for scavenging reactive oxygen species and for preserving the redox regulatory activity of Trx. S-nitrosylation of Trx also contributes to the anti-apoptotic function of Trx. Thus, Trx can exert its complete redox regulatory and anti-apoptotic functions in endothelial cells only when cysteine 69 is S-nitrosylated.

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Figure 1: Trx is essential for S-NO content in endothelial cells.
Figure 2: Trx is S-nitrosylated at Cys 69.
Figure 3: S-nitrosylation of Cys 69 is essential for the redox regulatory function of Trx.
Figure 4: Maintenance of the intracellular S-NO content by Trx depends on the production of endogenous NO.
Figure 5: S-nitrosylation of Cys 69 is required for the anti-apoptotic functions of Trx in endothelial cells.

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References

  1. Holmgren, A. Thioredoxin and glutaredoxin systems. J. Biol. Chem. 264, 13963–13966 (1989).

    CAS  PubMed  Google Scholar 

  2. Nordberg, J. & Arner, E. S. Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. Free Radic. Biol. Med. 31, 1287–1312 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Matsui, M. et al. Early embryonic lethality caused by targeted disruption of the mouse thioredoxin gene. Dev. Biol. 178, 179–185 (1996).

    Article  CAS  PubMed  Google Scholar 

  4. Reichard, P. From RNA to DNA, why so many ribonucleotide reductases? Science 260, 1773–1777 (1993).

    Article  CAS  PubMed  Google Scholar 

  5. Lundstrom, J. & Holmgren, A. Protein disulfide-isomerase is a substrate for thioredoxin reductase and has thioredoxin-like activity. J. Biol. Chem. 265, 9114–9120 (1990).

    CAS  PubMed  Google Scholar 

  6. Tanaka, T. et al. Redox regulation by thioredoxin superfamily: protection against oxidative stress and aging. Free Radic. Res. 33, 851–855 (2001).

    Article  Google Scholar 

  7. Hirota, K. et al. AP-1 transcriptional activity is regulated by a direct association between thioredoxin and Ref-1. Proc. Natl Acad. Sci. USA 94, 3633–3638 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Matthews, J. R., Wakasugi, N., Virelizier, J. L., Yodoi, J. & Hay, R. T. Thioredoxin regulates the DNA binding activity of NF-κB by reduction of a disulphide bond involving cysteine 62. Nucleic Acids Res. 20, 3821–3830 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Schenk, H., Klein, M., Erdbrugger, W., Droge, W. & Schulze-Osthoff, K. Distinct effects of thioredoxin and antioxidants on the activation of transcription factors NF-κB and AP-1. Proc. Natl Acad. Sci. USA 91, 1672–1676 (1994).

    Article  CAS  PubMed  Google Scholar 

  10. Saitoh, M. et al. Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J. 17, 2596–2606 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Moncada, S. & Higgs, A. The l-arginine-nitric oxide pathway. N. Engl. J. Med. 329, 2002–2012 (1993).

    Article  CAS  PubMed  Google Scholar 

  12. Harrison, D. G. Endothelial dysfunction in atherosclerosis. Basic Res. Cardiol. 1, 87–102 (1994).

    Google Scholar 

  13. Tsao, P. S. & Cooke, J. P. Endothelial alterations in hypercholesterolemia: more than simply vasodilator dysfunction. J. Cardiovasc. Pharmacol. 32 (Suppl. 3), S48–S53 (1998).

    CAS  PubMed  Google Scholar 

  14. Murohara, T. et al. Role of endothelial nitric oxide synthase in endothelial cell migration. Arterioscler. Thromb. Vasc. Biol. 19, 1156–1161 (1999).

    Article  CAS  PubMed  Google Scholar 

  15. Dimmeler, S. & Zeiher, A. M. Nitric oxide — an endothelial cell survival factor. Cell Death Differ. 6, 964–968 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Stamler, J. S. et al. S-nitrosylation of proteins with nitric oxide: synthesis and characterization of biologically active compounds. Proc. Natl Acad. Sci. USA 89, 444–448 (1992).

    Article  CAS  PubMed  Google Scholar 

  17. Liu, L. & Stamler, J. S. NO: an inhibitor of cell death. Cell Death Differ. 6, 937–942 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Melino, G. et al. S-nitrosylation regulates apoptosis. Nature 388, 432–433 (1997).

    Article  CAS  PubMed  Google Scholar 

  19. Eu, J. P., Liu, L., Zeng, M. & Stamler, J. S. An apoptotic model for nitrosative stress. Biochemistry 39, 1040–1047 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Hoffmann, J., Haendeler, J., Zeiher, A. M. & Dimmeler, S. TNF-α and oxLDL induce a denitrosylation of proteins in endothelial cells. J. Biol. Chem. 276, 41383–41387 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Stamler, J. S., Lamas, S. & Fang, F. C. Nitrosylation. the prototypic redox-based signaling mechanism. Cell 106, 675–683 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Mannick, J. B. et al. Fas-induced caspase denitrosylation. Science 284, 651–654 (1999).

    Article  CAS  Google Scholar 

  23. Stamler, J. S., Toone, E. J., Lipton, S. A. & Sucher, N. J. SNO signals: translocation, regulation, and a consensus motif. Neuron 18, 691–696 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. Stamler, J. S. & Hausladen, A. Oxidative modifications in nitrosative stress. Nature Struct. Biol. 5, 247–249 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. Jaffrey, S. R., Erdjument-Bromage, H., Ferris, C. D., Tempst, P. & Snyder, S. H. Protein S-nitrosylation: a physiological signal for neuronal nitric oxide. Nature Cell Biol. 3, 193–197 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Dalton, T. P., Shertzer, H. G. & Puga, A. Regulation of gene expression by reactive oxygen. Annu. Rev. Pharmacol. Toxicol. 39, 67–101 (1999).

    Article  CAS  PubMed  Google Scholar 

  27. Nakamura, H., Nakamura, K. & Yodoi, J. Redox regulation of cellular activation. Annu. Rev. Immunol. 15, 351–369 (1997).

    Article  CAS  PubMed  Google Scholar 

  28. Andoh, T., Chock, P. B. & Chiueh, C. C. The roles of thioredoxin in protection against oxidative stress-induced apoptosis in SH-SY5Y cells. J. Biol. Chem. 277, 9655–9660 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Baker, A., Payne, C. M., Briehl, M. M. & Powis, G. Thioredoxin, a gene found overexpressed in human cancer, inhibits apoptosis in vitro and in vivo. Cancer Res. 57, 5162–5167 (1997).

    CAS  PubMed  Google Scholar 

  30. Abello, P. A., Fidler, S. A. & Buchman, T. G. Thiol reducing agents modulate induced apoptosis in porcine endothelial cells. Shock 2, 79–83 (1994).

    Article  CAS  PubMed  Google Scholar 

  31. Dimmeler, S. & Zeiher, A. M. Reactive oxygen species and vascular cell apoptosis in response to angiotensin II and pro-atherosclerotic factors. Regul. Pept. 90, 19–25 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Chandra, J., Samali, A. & Orrenius, S. Triggering and modulation of apoptosis by oxidative stress. Free Radic. Biol. Med. 29, 323–333 (2000).

    Article  CAS  PubMed  Google Scholar 

  33. Bayraktutan, U., Blayney, L. & Shah, A. M. Molecular characterization and localization of the NAD(P)H oxidase components gp91-phox and p22-phox in endothelial cells. Arterioscler. Thromb. Vasc. Biol. 20, 1903–1911 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Li, J., Billiar, T. R., Talanian, R. V. & Kim, Y. M. Nitric oxide reversibly inhibits seven members of the caspase family via S-nitrosylation. Biochem. Biophys. Res. Commun. 240, 419–424 (1997).

    Article  CAS  PubMed  Google Scholar 

  35. Dimmeler, S., Haendeler, J., Nehls, M. & Zeiher, A. M. Suppression of apoptosis by nitric oxide via inhibition of ICE-like and CPP32-like proteases. J. Exp. Med. 185, 601–608 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Haendeler, J., Weiland, U., Zeiher, A. M. & Dimmeler, S. Effects of redox-related congeners on apoptosis and caspase-3 activity. Nitric Oxide 1, 282–293 (1997).

    Article  CAS  PubMed  Google Scholar 

  37. Tenneti, L., D'Emilia, D. M. & Lipton, S. A. Suppression of neuronal apoptosis by S-nitrosylation of caspases. Neurosci. Lett. 236, 139–142 (1997)

    Article  CAS  PubMed  Google Scholar 

  38. Eu, J. P., Sun, J., Xu, L., Stamler, J. S. & Meissner, G. The skeletal muscle calcium release channel: coupled O2 sensor and NO signaling functions. Cell 102, 499–509 (2000).

    Article  CAS  Google Scholar 

  39. Pawloski, J. R., Hess, D. T. & Stamler, J. S. Export by red blood cells of nitric oxide bioactivity. Nature 409, 622–626 (2001).

    Article  CAS  Google Scholar 

  40. Sun, J., Xin, C., Eu, J. P., Stamler, J. S. & Meissner, G. Cysteine-3635 is responsible for skeletal muscle ryanodine receptor modulation by NO. Proc. Natl Acad. Sci. USA 98, 11158–11162 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Haendeler, J., Ishida, M., Hunyady, L. & Berk, B. C. The third cytoplasmic loop of the angiotensin II type 1 receptor exerts differential effects on extracellular signal-regulated kinase (ERK1/ERK2) and apoptosis via Ras- and Rap1-dependent pathways. Circ. Res. 86, 729–736 (2000).

    Article  CAS  Google Scholar 

  42. Dimmeler, S., Haendeler, J., Galle, J. & Zeiher, A. M. Oxidized low density lipoprotein induces apoptosis of human endothelial cells by activation of CPP32-like proteases: a mechanistic clue to the response to injury hypothesis. Circulation 95, 1760–1763 (1997).

    Article  CAS  PubMed  Google Scholar 

  43. Park, H. S., Huh, S. H., Kim, M. S., Lee, S. H. & Choi, E. J. Nitric oxide negatively regulates c-Jun N-terminal kinase/stress-activated protein kinase by means of S-nitrosylation. Proc. Natl Acad. Sci. USA 97, 14022–14024 (2000).

    Article  Google Scholar 

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Acknowledgements

We thank C. Goy for technical assistance. This work was supported by a grant to S.D. from the Deutsche Forschungsgesellschaft, Sonderforschungsbereich. J. Haendeler was supported by a grant from the Deutsche Forschungsgesellschaft. J. Hoffmann was supported by a stipendium from Boehringer Ingelheim Fonds.

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Authors and Affiliations

  1. Department of Internal Medicine IV, Molecular Cardiology, University of Frankfurt, Theodor-Stern-Kai 7, Frankfurt, 60590, Germany

    Judith Haendeler, Jörg Hoffmann, Verena Tischler, Andreas M. Zeiher & Stefanie Dimmeler

  2. Center for Cardiovascular Research, University of Rochester, 601 Elmwood Ave, Box 679, Rochester, 14642, New York, USA

    Bradford C. Berk

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Correspondence to Stefanie Dimmeler.

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Haendeler, J., Hoffmann, J., Tischler, V. et al. Redox regulatory and anti-apoptotic functions of thioredoxin depend on S-nitrosylation at cysteine 69. Nat Cell Biol 4, 743–749 (2002). https://doi.org/10.1038/ncb851

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