Abstract
“Two-cysteine” peroxiredoxins are antioxidant enzymes that exert a cytoprotective effect in many models of oxidative stress. However, under highly oxidizing conditions they can be inactivated through hyperoxidation of their peroxidatic active site cysteine residue. Sulfiredoxin can reverse this hyperoxidation, thus reactivating peroxiredoxins. Here we review recent investigations that have shed further light on sulfiredoxin’s role and regulation. Studies have revealed sulfiredoxin to be a dynamically regulated gene whose transcription is induced by a variety of signals and stimuli. Sulfiredoxin expression is regulated by the transcription factor AP-1, which mediates its up-regulation by synaptic activity in neurons, resulting in protection against oxidative stress. Furthermore, sulfiredoxin has been identified as a new member of the family of genes regulated by Nuclear factor erythroid 2-related factor (Nrf2) via a conserved Åáë-acting antioxidant response element (ARE). As such, sulfiredoxin is likely to contribute to the net antioxidative effect of small molecule activators of Nrf2. As discussed here, the proximal AP-1 site of the sulfiredoxin promoter is embedded within the ARE, as is common with Nrf2 target genes. Other recent studies have shown that sulfiredoxin induction via Nrf2 may form an important part of the protective response to oxidative stress in the lung, preventing peroxiredoxin hyperoxidation and, in certain cases, subsequent degradation. We illustrate here that sulfiredoxin can be rapidly induced in vivo by administration of CDDO-TFEA, a synthetic triterpenoid inducer of endogenous Nrf2, which may offer a way of reversing peroxiredoxin hyperoxidation in vivo following chronic or acute oxidative stress.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bae, S.H., Woo, H.A., Sung, S.H., Lee, H.E., Lee, S.K., Kil, I.S., and Rhee, S.G. (2009). Induction of sulfiredoxin via an Nrf2- dependent pathway and hyperoxidation of peroxiredoxin III in the lungs of mice exposed to hyperoxia. Antioxid. Redox Signal. [Epub ahead of print]
Biteau, B., Labarre, J., and Toledano, M.B. (2003). ATP-dependent reduction of cysteine-sulphinic acid by S. cerevisiae sulphiredoxin. Nature 425, 980–984.
Boulos, S., Meloni, B.P., Arthur, P.G., Bojarski, C., and Knuckey, N.W. (2007). Peroxiredoxin 2 overexpression protects cortical neuronal cultures from ischemic and oxidative injury but not glutamate excitotoxicity, whereas Cu/Zn superoxide dismutase 1 overexpression protects only against oxidative injury. J. Neurosci. Res. 85, 3089–3097.
Brown, P.H., Alani, R., Preis, L.H., Szabo, E., and Birrer, M.J. (1993). Suppression of oncogene-induced transformation by a deletion mutant of c-jun. Oncogene 8, 877–886.
Budanov, A.V., Sablina, A.A., Feinstein, E., Koonin, E.V., and Chumakov, P.M. (2004). Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD. Science 304, 596–600.
Chang, T.S., Jeong, W., Woo, H.A., Lee, S.M., Park, S., and Rhee, S.G. (2004). Characterization of mammalian sulfiredoxin and its reactivation of hyperoxidized peroxiredoxin through reduction of cysteine sulfinic acid in the active site to cysteine. J. Biol. Chem. 279, 50994–51001.
Fang, J., Nakamura, T., Cho, D.H., Gu, Z., and Lipton, S.A. (2007). S-nitrosylation of peroxiredoxin 2 promotes oxidative stressinduced neuronal cell death in Parkinson’s disease. Proc. Natl. Acad. Sci. USA 104, 18742–18747.
Findlay, V.J., Townsend, D.M., Morris, T.E., Fraser, J.P., He, L., and Tew, K.D. (2006). A novel role for human sulfiredoxin in the reversal of glutathionylation. Cancer Res. 66, 6800–6806.
Giudice, A., and Montella, M. (2006). Activation of the Nrf2-ARE signaling pathway: a promising strategy in cancer prevention. Bioessays 28, 169–181.
Glauser, D.A., Brun, T., Gauthier, B.R., and Schlegel, W. (2007). Transcriptional response of pancreatic beta cells to metabolic stimulation: large scale identification of immediate-early and secondary response genes. BMC Mol. Biol. 8, 54.
Hattori, F., Murayama, N., Noshita, T., and Oikawa, S. (2003). Mitochondrial peroxiredoxin-3 protects hippocampal neurons from excitotoxic injury in vivo. J. Neurochem. 86, 860–868.
Immenschuh, S., and Baumgart-Vogt, E. (2005). Peroxiredoxins, oxidative stress, and cell proliferation. Antioxid. Redox Signal. 77, 768–777.
Jeong, W., Park, S.J., Chang, T.S., Lee, D.Y., and Rhee, S.G. (2006). Molecular mechanism of the reduction of cysteine sulfinic acid of peroxiredoxin to cysteine by mammalian sulfiredoxin. J. Biol. Chem. 281, 14400–14407.
Jonsson, T.J., Johnson, L.C., and Lowther, W.T. (2008a). Structure of the sulphiredoxin-peroxiredoxin complex reveals an essential repair embrace. Nature 451, 98–101.
Jonsson, T.J., Murray, M.S., Johnson, L.C., and Lowther, W.T. (2008b). Reduction of cysteine sulfinic acid in peroxiredoxin by sulfiredoxin proceeds directly through a sulfinic phosphoryl ester intermediate. J. Biol. Chem. 283, 23846–23851.
Kensler, T.W., Wakabayashi, N., and Biswal, S. (2007). Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu. Rev. Pharmacol. Toxicol. 47, 89–116.
Lee, J.M., Li, J., Johnson, D.A., Stein, T.D., Kraft, A.D., Calkins, M.J., Jakel, R.J., and Johnson, J.A. (2005). Nrf2, a multi-organ protector? FASEB J. 19, 1061–1066.
Liby, K.T., Yore, M.M., and Sporn, M.B. (2007). Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer. Nat. Rev. Cancer 7, 357–369.
Nguyen, T., Yang, C.S., and Pickett, C.B. (2004). The pathways and molecular mechanisms regulating Nrf2 activation in response to chemical stress. Free Radic. Biol. Med. 37, 433–441.
Nioi, P., McMahon, M., Itoh, K., Yamamoto, M., and Hayes, J.D. (2003). Identification of a novel Nrf2-regulated antioxidant response element (ARE) in the mouse NAD(P)H:quinone oxidoreductase 1 gene: reassessment of the ARE consensus sequence. Biochem. J. 374, 337–348.
Noh, Y.H., Baek, J.Y., Jeong, W., Rhee, S.G., and Chang, T.S. (2009). Sulfiredoxin translocation into mitochondria plays a crucial role in reducing hyperoxidized peroxiredoxin III. J. Biol. Chem. doi:10.1074/jbc.M808981200.
Papadia, S., Soriano, F.X., Leveille, F., Martel, M.A., Dakin, K.A., Hansen, H.H., Kaindl, A., Sifringer, M., Fowler, J., Stefovska, V., et al. (2008). Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses. Nat. Neurosci. 11, 476–487.
Qu, D., Rashidian, J., Mount, M.P., Aleyasin, H., Parsanejad, M., Lira, A., Haque, E., Zhang, Y., Callaghan, S., Daigle, M., et al. (2007). Role of Cdk5-mediated phosphorylation of Prx2 in MPTP toxicity and Parkinson’s disease. Neuron 55, 37–52.
Rhee, S.G., Chae, H.Z., and Kim, K. (2005). Peroxiredoxins: a historical overview and speculative preview of novel mechanisms and emerging concepts in cell signaling. Free Radic. Biol. Med. 38, 1543–1552.
Rhee, S.G., Jeong, W., Chang, T.S., and Woo, H.A. (2007). Sulfiredoxin, the cysteine sulfinic acid reductase specific to 2-Cys peroxiredoxin: its discovery, mechanism of action, and biological significance. Kidney Int. 106, S3–8.
Rhee, S.G., Woo, H.A., Bae, S.H., and Park, S. (2009) Sestrin 2 is not a reductase for cysteine sulfinic acid of peroxiredoxins. Antioxid. Redox Signal. 11, 739–745. (in press).
Sanchez-Font, M.F., Sebastia, J., Sanfeliu, C., Cristofol, R., Marfany, G., and Gonzalez-Duarte, R. (2003). Peroxiredoxin 2 (PRDX2), an antioxidant enzyme, is under-expressed in Down syndrome fetal brains. Cell Mol. Life Sci. 60, 1513–1523.
Shih, A.Y., Li, P., and Murphy, T.H. (2005). A small-molecule-inducible Nrf2-mediated antioxidant response provides effective prophylaxis against cerebral ischemia in vivo. J. Neurosci. 25, 10321–10335.
Singh, A., Ling, G., Suhasini, A.N., Zhang, P., Yamamoto, M., Navas-Acien, A., Cosgrove, G., Tuder, R.M., Kensler, T.W., Watson, W.H., et al. (2009). Nrf2-dependent sulfiredoxin-1 expression protects against cigarette smoke-induced oxidative stress in lungs. Free Radic. Biol. Med. 46, 376–386.
Soriano, F.X., Leveille, F., Papadia, S., Higgins, L.G., Varley, J., Baxter, P., Hayes, J.D., and Hardingham, G.E. (2008). Induction of sulfiredoxin expression and reduction of peroxiredoxin hyperoxidation by the neuroprotective Nrf2 activator 3H-1,2-dithiole-3-thione. J. Neurochem. 107, 533–543.
Wasserman, W.W., and Fahl, W.E. (1997). Comprehensive analysis of proteins which interact with the antioxidant responsive element: correlation of ARE-BP-1 with the chemoprotective induction response. Arch. Biochem. Biophys. 344, 387–396.
Wei, Q., Jiang, H., Matthews, C.P., and Colburn, N.H. (2008). Sulfiredoxin is an AP-1 target gene that is required for transformation and shows elevated expression in human skin malignancies. Proc. Natl. Acad. Sci. USA 105, 19738–19743.
Wood, Z.A., Schroder, E., Robin Harris, J., and Poole, L.B. (2003). Structure, mechanism and regulation of peroxiredoxins. Trends Biochem. Sci. 28, 32–40.
Yao, J., Taylor, M., Davey, F., Ren, Y., Aiton, J., Coote, P., Fang, F., Chen, J.X., Yan, S.D., and Gunn-Moore, F.J. (2007). Interaction of amyloid binding alcohol dehydrogenase/Abeta mediates up-regulation of peroxiredoxin II in the brains of Alzheimer’s disease patients and a transgenic Alzheimer’s disease mouse model. Mol. Cell. Neurosci., 377–382.
Yates, M.S., Tauchi, M., Katsuoka, F., Flanders, K.C., Liby, K.T., Honda, T., Gribble, G.W., Johnson, D.A., Johnson, J.A., Burton, N.C., et al. (2007). Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes. Mol. Cancer Ther. 6, 154–162.
Zhang, D.D. (2006). Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab. Rev. 38, 769–789.
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Soriano, F.X., Baxter, P., Murray, L.M. et al. Transcriptional regulation of the AP-1 and Nrf2 target gene sulfiredoxin. Mol Cells 27, 279–282 (2009). https://doi.org/10.1007/s10059-009-0050-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10059-009-0050-y