Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Brief Communication
  • Published:

Arfaptin 2 regulates the aggregation of mutant huntingtin protein

Nature Cell Biology volume 4, pages 240–245 (2002)Cite this article

Abstract

Huntington's disease (HD) is an inherited neurodegenerative disorder. Here we demonstrate that expression of arfaptin 2/POR1 (partner of Rac1) in cultured cells induces the formation of pericentriolar and nuclear aggregates, which morphologically resemble mutant huntingtin aggregates characteristic of HD. Endogenous arfaptin 2 localizes to aggregates induced by expression of an abnormal amino-terminal fragment of huntingtin that contains polyglutamine (polyQ) expansions. A dominant inhibitory mutant of arfaptin 2 inhibits aggregation of mutant huntingtin, but not in the presence of proteasome inhibitors. Using cell-free biochemical assays, we show that arfaptin 2 inhibits proteasome activity. Finally, we show that expression of arfaptin 2 is increased at sites of neurodegeneration and the protein localizes to huntingtin aggregates in HD transgenic mouse brains. Our data suggest that arfaptin 2 is involved in regulating huntingtin protein aggregation, possibly by impairing proteasome function.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Localization of arfaptin 2.
Figure 2: Arfaptin-2-induced aggregates contain huntingtin and mutant-huntingtin-induced aggregates contain arfaptin 2.
Figure 3: Effect of mutant arfaptin 2 on GFP–HttexpolyQ aggregation.
Figure 4: Lactacystin reverses the effect of DN-arfaptin 2 on huntingtin aggregation.
Figure 5: Detection of arfaptin 2 in R6/2 transgenic HD brains.

Similar content being viewed by others

References

  1. The Huntington's Disease Collaborative Research Group. Cell 72, 971–983 (1993).

  2. Mangiarini, L. et al. Cell 87, 493–506 (1996).

    Article  CAS  Google Scholar 

  3. Wanker, E. E. J. Biol. Chem. 381, 937–942 (2000).

    CAS  Google Scholar 

  4. Sathasivam, K. et al. Hum. Mol. Genet. 8, 813–822 (1999).

    Article  CAS  Google Scholar 

  5. Kanoh, H., Williger, B. T. & Exton, J. H. J. Biol. Chem. 272, 5421–5429 (1997).

    Article  CAS  Google Scholar 

  6. D'Souza-Schorey, C., Boshans, R. L., McDonough, M., Stahl, P. D. & Van Aelst, L. EMBO J. 16, 5445–5454 (1997).

    Article  CAS  Google Scholar 

  7. Van Aelst, L., Joneson, T. & Bar-Sagi, D. EMBO J. 15, 3778–3786 (1996).

    Article  CAS  Google Scholar 

  8. Shin, O. H. & Exton, J. H. Biochem. Biophys. Res. Commun. 285, 1267–1273 (2001).

    Article  CAS  Google Scholar 

  9. Sherman, M. Y. & Goldberg, A. L. Neuron 29, 15–32 (2001).

    Article  CAS  Google Scholar 

  10. Waelter, S. et al. Mol. Biol. Cell 12, 1393–1407 (2001).

    Article  CAS  Google Scholar 

  11. Suhr, S. T. et al. J. Cell Biol. 153, 283–294 (2001).

    Article  CAS  Google Scholar 

  12. Sittler, A. et al. Hum. Mol. Genet. 10, 1307–1315 (2001).

    Article  CAS  Google Scholar 

  13. Sittler, A. et al. Mol. Cell 2, 427–436 (1998).

    Article  CAS  Google Scholar 

  14. Krobitsch, S. & Lindquist, S. Proc. Natl Acad. Sci. USA 97, 1589–1594 (2000).

    Article  CAS  Google Scholar 

  15. Muchowski, P. J. et al. Proc. Natl Acad. Sci. USA 97, 7841–7846 (2000).

    Article  CAS  Google Scholar 

  16. Carmichael, J. et al. Proc. Natl Acad. Sci. USA 97, 9701–9705 (2000).

    Article  CAS  Google Scholar 

  17. Meriin, A. B. et al. J. Cell Biol. 153, 851–864 (2001).

    Article  CAS  Google Scholar 

  18. Chun, W., Lesort, M., Tucholski, J., Ross, C. A. & Johnson, G. V. J. Cell Biol. 153, 25–34 (2001).

    Article  CAS  Google Scholar 

  19. Karpuj, M. V. et al. Proc. Natl Acad. Sci. USA 96, 7388–7393 (1999).

    Article  CAS  Google Scholar 

  20. Kahlem, P., Green, H. & Djian, P. Mol. Cell 1, 595–601 (1998).

    Article  CAS  Google Scholar 

  21. Wigley, W. C. et al. J. Cell Biol. 145, 481–490 (1999).

    Article  CAS  Google Scholar 

  22. Bence, N. F., Sampat, R. M. & Kopito, R. R. Science 292, 1552–1555 (2001).

    Article  CAS  Google Scholar 

  23. Tarricone, C. et al. Nature 411, 215–219 (2001).

    Article  CAS  Google Scholar 

  24. Mineo, C., Gill, G. N. & Anderson, R. G. J. Biol. Chem. 274, 30636–30643 (1999).

    Article  CAS  Google Scholar 

  25. Johnston, J. A., Ward, C. L. & Kopito, R. R. J. Cell Biol. 143, 1883–1898 (1998).

    Article  CAS  Google Scholar 

  26. Kazantsev, A., Preisinger, E., Dranovsky, A., Goldgaber, D. & Housman, D. Proc. Natl Acad. Sci. USA 96, 11404–11409 (1999).

    Article  CAS  Google Scholar 

  27. Dorsman, J. C. et al. Philos. Trans. R. Soc. Lond. B Biol. Sci. 354, 1061–1067 (1999).

    Article  CAS  Google Scholar 

  28. Davies, S. W. et al. Methods Enzymol. 309, 687–701 (1999).

    Article  CAS  Google Scholar 

  29. Boshans, R. L., Szanto, S., van Aelst, L. & D'Souza-Schorey, C. Mol. Cell Biol. 20, 3685–3694 (2000).

    Article  CAS  Google Scholar 

  30. D'Souza-Schorey, C. et al. J. Cell Biol. 140, 603–616 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank E. Signer, and J. Schweitzer for discussions and critical reading of the manuscript. We thank J. Exton for arfaptin 2 cDNA, J. Dorsman for huntingtin antibodies, E. Van Donselaar and Erik Bos for excellent technical assistance with EM procedures, A. Mahal for genotyping the mice, O. Spasic-Boscovic for assistance with immunocytochemistry and B. Apostal for assistance with generating the cell line expressing GFP–HttexpolyQ. We acknowledge the EM division of Utrecht University for excellent technical assistance with photography and handling of EM micrographs. This work was supported in part by grants from the Hereditary Diseases Foundation, Cure HD Initiative, to C.D.-S and L.T., and by grants from the Human Science Frontiers Program and the Wellcome Trust to G.B.

Author information

Author notes

  1. Peter J. Peters and Ke Ning: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biological Sciences, and the Walther Cancer Institute, University of Notre Dame, Notre Dame, 46556, Indiana, USA

    Ke Ning, Felipe Palacios, Rita L. Boshans & Crislyn D'Souza-Schorey

  2. Department of Cell Biology, Utrecht University Medical School, Utrecht, Amsterdam, The Netherlands

    Peter J. Peters

  3. Division of Tumor Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Peter J. Peters

  4. Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Aleksey Kazantsev

  5. Department of Biological Chemistry, Psychiatry and Behavioral Science, University of California at Irvine, Irvine, 92697, California, USA

    Leslie M. Thompson

  6. Division of Medical and Molecular Genetics, Guy's and St Thomas's School of Medicine, London, SE1 9RT, UK

    Ben Woodman & Gillian P. Bates

Authors
  1. Peter J. Peters
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ke Ning
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Felipe Palacios
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rita L. Boshans
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aleksey Kazantsev
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Leslie M. Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ben Woodman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gillian P. Bates
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Crislyn D'Souza-Schorey
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Crislyn D'Souza-Schorey.

Supplementary information

Figure S1

Cytoplasmic distribution of arfaptin 2. (PDF 1310 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Peters, P., Ning, K., Palacios, F. et al. Arfaptin 2 regulates the aggregation of mutant huntingtin protein. Nat Cell Biol 4, 240–245 (2002). https://doi.org/10.1038/ncb761

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb761

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing