S-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration (original) (raw)

Nature volume 441, pages 513–517 (2006)Cite this article

Abstract

Stress proteins located in the cytosol or endoplasmic reticulum (ER) maintain cell homeostasis and afford tolerance to severe insults1,2,3. In neurodegenerative diseases, several chaperones ameliorate the accumulation of misfolded proteins triggered by oxidative or nitrosative stress, or of mutated gene products4,5. Although severe ER stress can induce apoptosis2,6, the ER withstands relatively mild insults through the expression of stress proteins or chaperones such as glucose-regulated protein (GRP) and protein-disulphide isomerase (PDI), which assist in the maturation and transport of unfolded secretory proteins. PDI catalyses thiol–disulphide exchange, thus facilitating disulphide bond formation and rearrangement reactions7,8,9,10. PDI has two domains that function as independent active sites with homology to the small, redox-active protein thioredoxin7,8. During neurodegenerative disorders and cerebral ischaemia, the accumulation of immature and denatured proteins results in ER dysfunction11, but the upregulation of PDI represents an adaptive response to protect neuronal cells12,13,14. Here we show, in brains manifesting sporadic Parkinson's or Alzheimer's disease, that PDI is _S_-nitrosylated, a reaction transferring a nitric oxide (NO) group to a critical cysteine thiol to affect protein function15,16,17,18. NO-induced _S_-nitrosylation of PDI inhibits its enzymatic activity, leads to the accumulation of polyubiquitinated proteins, and activates the unfolded protein response. _S_-Nitrosylation also abrogates PDI-mediated attenuation of neuronal cell death triggered by ER stress, misfolded proteins or proteasome inhibition. Thus, PDI prevents neurotoxicity associated with ER stress and protein misfolding, but NO blocks this protective effect in neurodegenerative disorders through the _S_-nitrosylation of PDI.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 51 print issues and online access

$199.00 per year

only $3.90 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

References

  1. Ellgaard, L., Molinari, M. & Helenius, A. Setting the standards: quality control in the secretory pathway. Science 286, 1882–1888 (1999)
    Article CAS PubMed Google Scholar
  2. Kaufman, R. J. Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev. 13, 1211–1233 (1999)
    Article CAS PubMed Google Scholar
  3. Patil, C. & Walter, P. Intracellular signaling from the endoplasmic reticulum to the nucleus: the unfolded protein response in yeast and mammals. Curr. Opin. Cell Biol. 13, 349–355 (2001)
    Article CAS PubMed Google Scholar
  4. Rao, R. V. & Bredesen, D. E. Misfolded proteins, endoplasmic reticulum stress and neurodegeneration. Curr. Opin. Cell Biol. 16, 653–662 (2004)
    Article CAS PubMed PubMed Central Google Scholar
  5. Haynes, C. M., Titus, E. A. & Cooper, A. A. Degradation of misfolded proteins prevents ER-derived oxidative stress and cell death. Mol. Cell 15, 767–776 (2004)
    Article CAS PubMed Google Scholar
  6. Imai, Y. et al. An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 105, 891–902 (2001)
    Article CAS PubMed Google Scholar
  7. Edman, J. C., Ellis, L., Blacher, R. W., Roth, R. A. & Rutter, W. J. Sequence of protein disulphide isomerase and implications of its relationship to thioredoxin. Nature 317, 267–270 (1985)
    Article ADS CAS PubMed Google Scholar
  8. Vuori, K., Myllyla, R., Pihlajaniemi, T. & Kivirikko, K. I. Expression and site-directed mutagenesis of human protein disulfide isomerase in Escherichia coli. This multifunctional polypeptide has two independently acting catalytic sites for the isomerase activity. J. Biol. Chem. 267, 7211–7214 (1992)
    CAS PubMed Google Scholar
  9. Song, J. L. & Wang, C. C. Chaperone-like activity of protein disulfide-isomerase in the refolding of rhodanese. Eur. J. Biochem. 231, 312–316 (1995)
    Article CAS PubMed Google Scholar
  10. Gilbert, H. F. Protein disulfide isomerase. Methods Enzymol. 290, 26–50 (1998)
    Article CAS PubMed Google Scholar
  11. Hu, B. R., Martone, M. E., Jones, Y. Z. & Liu, C. L. Protein aggregation after transient cerebral ischemia. J. Neurosci. 20, 3191–3199 (2000)
    Article CAS PubMed PubMed Central Google Scholar
  12. Ko, H. S., Uehara, T. & Nomura, Y. Role of ubiquilin associated with protein-disulfide isomerase in the endoplasmic reticulum in stress-induced apoptotic cell death. J. Biol. Chem. 277, 35386–35392 (2002)
    Article CAS PubMed Google Scholar
  13. Tanaka, S., Uehara, T. & Nomura, Y. Up-regulation of protein-disulfide isomerase in response to hypoxia/brain ischemia and its protective effect against apoptotic cell death. J. Biol. Chem. 275, 10388–10393 (2000)
    Article CAS PubMed Google Scholar
  14. Conn, K. J. et al. Identification of the protein disulfide isomerase family member PDIp in experimental Parkinson's disease and Lewy body pathology. Brain Res. 1022, 164–172 (2004)
    Article CAS PubMed Google Scholar
  15. Lipton, S. A. et al. A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 364, 626–632 (1993)
    Article ADS CAS PubMed Google Scholar
  16. Stamler, J. S. Redox signaling: nitrosylation and related target interactions of nitric oxide. Cell 78, 931–936 (1994)
    Article CAS PubMed Google Scholar
  17. Haendeler, J. et al. Redox regulatory and anti-apoptotic functions of thioredoxin depend on _S_-nitrosylation at cysteine 69. Nature Cell Biol. 4, 743–749 (2002)
    Article CAS PubMed Google Scholar
  18. Sliskovic, I., Raturi, A. & Mutus, B. Characterization of the _S_-denitrosation activity of protein disulfide isomerase. J. Biol. Chem. 280, 8733–8741 (2005)
    Article CAS PubMed Google Scholar
  19. Gu, Z. et al. _S_-Nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science 297, 1186–1190 (2002)
    Article ADS CAS PubMed Google Scholar
  20. Yao, D. et al. Nitrosative stress linked to sporadic Parkinson's disease: _S_-nitrosylation of parkin regulates its E3 ubiquitin ligase activity. Proc. Natl Acad. Sci. USA 101, 10810–10814 (2004)
    Article ADS CAS PubMed PubMed Central Google Scholar
  21. 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
  22. Betarbet, R. et al. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nature Neurosci. 3, 1301–1306 (2000)
    Article CAS PubMed Google Scholar
  23. Nishikawa, A. et al. Novel function of PS2V: change in conformation of tau proteins. Biochem. Biophys. Res. Commun. 318, 435–438 (2004)
    Article CAS PubMed Google Scholar
  24. Bonfoco, E., Krainc, D., Ankarcrona, M., Nicotera, P. & Lipton, S. A. Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with _N_-methyl-d-aspartate or nitric oxide/superoxide in cortical cell cultures. Proc. Natl Acad. Sci. USA 92, 7162–7166 (1995)
    Article ADS CAS PubMed PubMed Central Google Scholar
  25. Dawson, V. L., Dawson, T. M., London, E. D., Bredt, D. S. & Snyder, S. H. Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc. Natl Acad. Sci. USA 88, 6368–6371 (1991)
    Article ADS CAS PubMed PubMed Central Google Scholar
  26. Lipton, S. A. & Rosenberg, P. A. Excitatory amino acids as a final common pathway for neurologic disorders. N. Engl. J. Med. 330, 613–622 (1994)
    Article CAS PubMed Google Scholar
  27. Hara, M. R. et al. _S_-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding. Nature Cell Biol. 7, 665–674 (2005)
    Article CAS PubMed Google Scholar
  28. Murakami, T. et al. Pael-R is accumulated in Lewy bodies of Parkinson's disease. Ann. Neurol. 55, 439–442 (2004)
    Article CAS PubMed Google Scholar
  29. Ryu, E. J. et al. Endoplasmic reticulum stress and the unfolded protein response in cellular models of Parkinson's disease. J. Neurosci. 22, 10690–10698 (2002)
    Article CAS PubMed PubMed Central Google Scholar
  30. Chung, K. K. et al. _S_-Nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function. Science 304, 1328–1331 (2004)
    Article ADS CAS PubMed Google Scholar

Download references

Acknowledgements

We thank X. Fang for preparation of cerebrocortical cultures, T. William for technical assistance with the analysis of mass spectra, and R. Takahashi for the Pael receptor construct. T.U. was supported in part by the Mitsubishi Pharma Research Foundation and a Grant-in-Aid from the Ministry of Education, Culture, Sports and Technology of Japan. S.A.L. was supported in part by grants from the NIH, the American Parkinson's Disease Association, San Diego Chapter, and an Ellison Senior Scholars Award in Aging. Author Contributions T.U. and T.N. performed most of the experiments, contributing equally to the work, and helped to write the manuscript. D.Y., Z.Q.S. and Z.G. provided the biochemical data, and also contributed equally to the work. Y.M. analyzed the mass spectrometry data. E.M. provided the human subjects, and Y.N. provided constructs and advice. S.A.L., the senior author, designed the project, helped to analyse the data, wrote the manuscript and provided the financial support.

Author information

Authors and Affiliations

  1. Center for Neuroscience and Aging,
    Takashi Uehara, Tomohiro Nakamura, Dongdong Yao, Zhong-Qing Shi, Zezong Gu & Stuart A. Lipton
  2. Proteomic Facility, Burnham Institute for Medical Research, La Jolla, 10901 North Torrey Pines Road, California, 92037, USA
    Yuliang Ma
  3. Department of Neurosciences, University of California at San Diego, La Jolla, 9500 Gilman Drive, California, 92039, USA
    Eliezer Masliah & Stuart A. Lipton
  4. Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, 060-0812, Japan
    Takashi Uehara & Yasuyuki Nomura

Authors

  1. Takashi Uehara
    You can also search for this author inPubMed Google Scholar
  2. Tomohiro Nakamura
    You can also search for this author inPubMed Google Scholar
  3. Dongdong Yao
    You can also search for this author inPubMed Google Scholar
  4. Zhong-Qing Shi
    You can also search for this author inPubMed Google Scholar
  5. Zezong Gu
    You can also search for this author inPubMed Google Scholar
  6. Yuliang Ma
    You can also search for this author inPubMed Google Scholar
  7. Eliezer Masliah
    You can also search for this author inPubMed Google Scholar
  8. Yasuyuki Nomura
    You can also search for this author inPubMed Google Scholar
  9. Stuart A. Lipton
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toStuart A. Lipton.

Ethics declarations

Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

About this article

Cite this article

Uehara, T., Nakamura, T., Yao, D. et al. _S_-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration.Nature 441, 513–517 (2006). https://doi.org/10.1038/nature04782

Download citation