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.

  • Article
  • Published:

Small-molecule proteostasis regulators for protein conformational diseases

Nature Chemical Biology volume 8, pages 185–196 (2012)Cite this article

Subjects

Abstract

Protein homeostasis (proteostasis) is essential for cellular and organismal health. Stress, aging and the chronic expression of misfolded proteins, however, challenge the proteostasis machinery and the vitality of the cell. Enhanced expression of molecular chaperones, regulated by heat shock transcription factor-1 (HSF-1), has been shown to restore proteostasis in a variety of conformational disease models, suggesting this mechanism as a promising therapeutic approach. We describe the results of a screen comprised of ∼900,000 small molecules that identified new classes of small-molecule proteostasis regulators that induce HSF-1–dependent chaperone expression and restore protein folding in multiple conformational disease models. These beneficial effects to proteome stability are mediated by HSF-1, FOXO, Nrf-2 and the chaperone machinery through mechanisms that are distinct from current known small-molecule activators of the heat shock response. We suggest that modulation of the proteostasis network by proteostasis regulators may be a promising therapeutic approach for the treatment of a variety of protein conformational diseases.

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: Identification of small-molecule proteostasis regulators by HTS.
Figure 2: The small-molecule proteostasis regulators induce Hsp expression by activating HSF-1.
Figure 3: The proteostasis regulators are HSF-1 dependent.
Figure 4: The proteostasis regulators restore proteostasis in cell-based models of cytoplasmic and compartment-specific conformational diseases.
Figure 5: The proteostasis regulators reduce aggregation and toxicity in C. elegans models of diseases associated with polyglutamine expansions.
Figure 6: Chaperone expression and reduction in polyglutamine aggregation in C. elegans is HSF-1 dependent.
Figure 7: The proteostasis regulators are not inhibitors of the proteasome or Hsp90.

Similar content being viewed by others

References

  1. Balch, W.E., Morimoto, R.I., Dillin, A. & Kelly, J.W. Adapting proteostasis for disease intervention. Science 319, 916–919 (2008).

    Article  CAS  Google Scholar 

  2. Powers, E.T., Morimoto, R.I., Dillin, A., Kelly, J.W. & Balch, W.E. Biological and chemical approaches to diseases of proteostasis deficiency. Annu. Rev. Biochem. 78, 959–991 (2009).

    Article  CAS  Google Scholar 

  3. Morimoto, R.I. Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging. Genes Dev. 22, 1427–1438 (2008).

    Article  CAS  Google Scholar 

  4. Ron, D. & Walter, P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 8, 519–529 (2007).

    Article  CAS  Google Scholar 

  5. Haynes, C.M. & Ron, D. The mitochondrial UPR - protecting organelle protein homeostasis. J. Cell Sci. 123, 3849–3855 (2010).

    Article  CAS  Google Scholar 

  6. Lichtlen, P. & Schaffner, W. Putting its fingers on stressful situations: the heavy metal-regulatory transcription factor MTF-1. Bioessays 23, 1010–1017 (2001).

    Article  CAS  Google Scholar 

  7. Vargas, M.R. & Johnson, J.A. The Nrf2-ARE cytoprotective pathway in astrocytes. Expert Rev. Mol. Med. 11, e17 (2009).

    Article  Google Scholar 

  8. Åkerfelt, M., Morimoto, R.I. & Sistonen, L. Heat shock factors: integrators of cell stress, development and lifespan. Nat. Rev. Mol. Cell Biol. 11, 545–555 (2010).

    Article  Google Scholar 

  9. Young, J.C., Agashe, V.R., Siegers, K. & Hartl, F.U. Pathways of chaperone-mediated protein folding in the cytosol. Nat. Rev. Mol. Cell Biol. 5, 781–791 (2004).

    Article  CAS  Google Scholar 

  10. Gidalevitz, T., Ben-Zvi, A., Ho, K.H., Brignull, H.R. & Morimoto, R.I. Progressive disruption of cellular protein folding in models of polyglutamine diseases. Science 311, 1471–1474 (2006).

    Article  CAS  Google Scholar 

  11. Gidalevitz, T., Kikis, E.A. & Morimoto, R.I. A cellular perspective on conformational disease: the role of genetic background and proteostasis networks. Curr. Opin. Struct. Biol. 20, 23–32 (2010).

    Article  CAS  Google Scholar 

  12. Sittler, A. et al. Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington′s disease. Hum. Mol. Genet. 10, 1307–1315 (2001).

    Article  CAS  Google Scholar 

  13. Muchowski, P.J. & Wacker, J.L. Modulation of neurodegeneration by molecular chaperones. Nat. Rev. Neurosci. 6, 11–22 (2005).

    Article  CAS  Google Scholar 

  14. Fujimoto, M. et al. Active HSF1 significantly suppresses polyglutamine aggregate formation in cellular and mouse models. J. Biol. Chem. 280, 34908–34916 (2005).

    Article  CAS  Google Scholar 

  15. Vacher, C., Garcia-Oroz, L. & Rubinsztein, D.C. Overexpression of yeast hsp104 reduces polyglutamine aggregation and prolongs survival of a transgenic mouse model of Huntington's disease. Hum. Mol. Genet. 14, 3425–3433 (2005).

    Article  CAS  Google Scholar 

  16. Waza, M. et al. 17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degeneration. Nat. Med. 11, 1088–1095 (2005).

    Article  CAS  Google Scholar 

  17. Zhang, Y.Q. & Sarge, K.D. Celastrol inhibits polyglutamine aggregation and toxicity though induction of the heat shock response. J. Mol. Med. 85, 1421–1428 (2007).

    Article  CAS  Google Scholar 

  18. Fujikake, N. et al. Heat shock transcription factor 1–activating compounds suppress polyglutamine-induced neurodegeneration through induction of multiple molecular chaperones. J. Biol. Chem. 283, 26188–26197 (2008).

    Article  CAS  Google Scholar 

  19. Hsu, A.L., Murphy, C.T. & Kenyon, C. Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 300, 1142–1145 (2003).

    Article  CAS  Google Scholar 

  20. Neef, D.W., Turski, M.L. & Thiele, D.J. Modulation of heat shock transcription factor 1 as a therapeutic target for small molecule intervention in neurodegenerative disease. PLoS Biol. 8, e1000291 (2010).

    Article  Google Scholar 

  21. Westerheide, S.D. & Morimoto, R.I. Heat shock response modulators as therapeutic tools for diseases of protein conformation. J. Biol. Chem. 280, 33097–33100 (2005).

    Article  CAS  Google Scholar 

  22. Taldone, T., Gozman, A., Maharaj, R. & Chiosis, G. Targeting Hsp90: small-molecule inhibitors and their clinical development. Curr. Opin. Pharmacol. 8, 370–374 (2008).

    Article  CAS  Google Scholar 

  23. Luo, W., Sun, W., Taldone, T., Rodina, A. & Chiosis, G. Heat shock protein 90 in neurodegenerative diseases. Mol. Neurodegener. 5, 24 (2010).

    Article  Google Scholar 

  24. Solit, D.B. et al. Phase II trial of 17-allylamino-17-demethoxygeldanamycin in patients with metastatic melanoma. Clin. Cancer Res. 14, 8302–8307 (2008).

    Article  CAS  Google Scholar 

  25. Westerheide, S.D. et al. Celastrols as inducers of the heat shock response and cytoprotection. J. Biol. Chem. 279, 56053–56060 (2004).

    Article  CAS  Google Scholar 

  26. Williams, G.T. & Morimoto, R.I. Maximal stress-induced transcription from the human HSP70 promoter requires interactions with the basal promoter elements independent of rotational alignment. Mol. Cell. Biol. 10, 3125–3136 (1990).

    Article  CAS  Google Scholar 

  27. Butina, D. Unsupervised data base clustering based on Daylight′s fingerprint and Tanimoto similarity: a fast and automated way to cluster small and large data sets. J. Chem. Inf. Comput. Sci. 39, 747–750 (1999).

    Article  CAS  Google Scholar 

  28. Amici, C., Sistonen, L., Santoro, M.G. & Morimoto, R.I. Antiproliferative prostaglandins activate heat shock transcription factor. Proc. Natl. Acad. Sci. USA 89, 6227–6231 (1992).

    Article  CAS  Google Scholar 

  29. Trott, A. et al. Activation of heat shock and antioxidant responses by the natural product celastrol: transcriptional signatures of a thiol-targeted molecule. Mol. Biol. Cell 19, 1104–1112 (2008).

    Article  CAS  Google Scholar 

  30. Li, C. et al. Pharmacologic induction of heme oxygenase-1. Antioxid. Redox Signal. 9, 2227–2239 (2007).

    Article  CAS  Google Scholar 

  31. Liu, Y. & Chang, A. Heat shock response relieves ER stress. EMBO J. 27, 1049–1059 (2008).

    Article  CAS  Google Scholar 

  32. Wyttenbach, A. et al. Polyglutamine expansions cause decreased CRE-mediated transcription and early gene expression changes prior to cell death in an inducible cell model of Huntington′s disease. Hum. Mol. Genet. 10, 1829–1845 (2001).

    Article  CAS  Google Scholar 

  33. Riordan, J.R. CFTR function and prospects for therapy. Annu. Rev. Biochem. 77, 701–726 (2008).

    Article  CAS  Google Scholar 

  34. Morley, J.F., Brignull, H.R., Weyers, J.J. & Morimoto, R.I. The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 99, 10417–10422 (2002).

    Article  Google Scholar 

  35. Nollen, E.A. et al. Genome-wide RNA interference screen identifies previously undescribed regulators of polyglutamine aggregation. Proc. Natl. Acad. Sci. USA 101, 6403–6408 (2004).

    Article  CAS  Google Scholar 

  36. Garcia, S.M., Casanueva, M.O., Silva, M.C., Amaral, M.D. & Morimoto, R.I. Neuronal signaling modulates protein homeostasis in Caenorhabditis elegans post-synaptic muscle cells. Genes Dev. 21, 3006–3016 (2007).

    Article  CAS  Google Scholar 

  37. Whitesell, L. & Lindquist, S.L. HSP90 and the chaperoning of cancer. Nat. Rev. Cancer 5, 761–772 (2005).

    Article  CAS  Google Scholar 

  38. Stringer, J.R., Bowman, M.D., Weisblum, B. & Blackwell, H.E. Improved small-molecule macroarray platform for the rapid synthesis and discovery of antibacterial chalcones. ACS Comb. Sci. 13, 175–180 (2011).

    Article  CAS  Google Scholar 

  39. Yadav, V.R., Prasad, S., Sung, B. & Aggarwal, B.B. The role of chalcones in suppression of NF-κB–mediated inflammation and cancer. Int. Immunopharmacol. 11, 295–309 (2010).

    Article  Google Scholar 

  40. Dinkova-Kostova, A.T., Massiah, M.A., Bozak, R.E., Hicks, R.J. & Talalay, P. Potency of Michael reaction acceptors as inducers of enzymes that protect against carcinogenesis depends on their reactivity with sulfhydryl groups. Proc. Natl. Acad. Sci. USA 98, 3404–3409 (2001).

    Article  CAS  Google Scholar 

  41. Dinkova-Kostova, A.T. et al. Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc. Natl. Acad. Sci. USA 99, 11908–11913 (2002).

    Article  CAS  Google Scholar 

  42. Tangallapally, R.P. et al. Synthesis and evaluation of nitrofuranylamides as novel antituberculosis agents. J. Med. Chem. 47, 5276–5283 (2004).

    Article  CAS  Google Scholar 

  43. Roesslein, M. et al. Thiopental protects human T lymphocytes from apoptosis in vitro via the expression of heat shock protein 70. J. Pharmacol. Exp. Ther. 325, 217–225 (2008).

    Article  CAS  Google Scholar 

  44. Yang, H. et al. Nanomolar affinity small molecule correctors of defective Δ F508-CFTR chloride channel gating. J. Biol. Chem. 278, 35079–35085 (2003).

    Article  CAS  Google Scholar 

  45. Yang, F. et al. Curcumin inhibits formation of amyloid β oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J. Biol. Chem. 280, 5892–5901 (2005).

    Article  CAS  Google Scholar 

  46. Teiten, M.H., Reuter, S., Schmucker, S., Dicato, M. & Diederich, M. Induction of heat shock response by curcumin in human leukemia cells. Cancer Lett. 279, 145–154 (2009).

    Article  CAS  Google Scholar 

  47. Mu, T.W. et al. Chemical and biological approaches synergize to ameliorate protein-folding diseases. Cell 134, 769–781 (2008).

    Article  CAS  Google Scholar 

  48. Parenti, G. Treating lysosomal storage diseases with pharmacological chaperones: from concept to clinics. EMBO Mol. Med. 1, 268–279 (2009).

    Article  CAS  Google Scholar 

  49. Gorbatyuk, M.S. et al. Restoration of visual function in P23H rhodopsin transgenic rats by gene delivery of BiP/Grp78. Proc. Natl. Acad. Sci. USA 107, 5961–5966 (2010).

    Article  CAS  Google Scholar 

  50. Tam, L.C. et al. Prevention of autosomal dominant retinitis pigmentosa by systemic drug therapy targeting heat shock protein 90 (Hsp90). Hum. Mol. Genet. 19, 4421–4436 (2010).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge J. Maddry, the SRI and the NINDS for support in performing the primary screen; P. Chase and P. Baillargeon of Scripps Florida for executing the SRIMSC screening activities; S. Fox, J. West, S. Westerheide, J. Moran, M. Beam and K. Orton for technical assistance; J.S. Pedersen for help developing the worm tracker system; and the Morimoto laboratory, in particular T. Gidalevitz, J. Kirstein, C. Voisine and A. Yu, for helpful comments. PC12 httQ74-GFP cells were provided by D. Rubinsztein (University of Cambridge). Purified Hsp90β was a gift of A. Chadli (Georgia Health Science University). We thank A. Ciechanover for the rabbit polyclonal ubiquitin antibody (Israel Institute of Technology). The CFBE41o- YFP cells were a gift from L. Galietta (Istituto Giannina Gaslini). This work was supported by the US National Institutes of Health (NIH) Training Grant in Signal Transduction and Cancer T32 CA70085 and the NIH Training Grant in Drug Discovery in Age Related Diseases T32 AG000260 (to B.C.), Portuguese PhD fellowship from the Fundação para a Ciência e Tecnologia (SFRH/BD/28461/2006) (to M.C.S.), NIH grants HL 079442, GM42336 and DK785483 (to W.E.B.), a fellowship from the Canadian Institutes for Health Research (CIHR) (to D.M.H.), the NIH Molecular Library Screening Center Network MH084512 (to F.M., S.A.S. and P.H.) and NIH grants GM038109, GM081192, AG026647 and NS047331 (to R.I.M.).

Author information

Authors and Affiliations

  1. Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois, USA

    Barbara Calamini, Maria Catarina Silva & Richard I Morimoto

  2. Faculty of Sciences, Centre for Biodiversity, Functional and Integrative Genomics (BioFIG), University of Lisboa, Lisboa, Portugal

    Maria Catarina Silva

  3. Lead Identification Division, Scripps Research Institute Molecular Screening Center, The Scripps Research Institute, Scripps Florida, Jupiter, Florida, USA.,

    Franck Madoux, S Adrian Saldanha & Peter Hodder

  4. Department of Cell Biology and Chemical Physiology, Institute for Childhood and Neglected Diseases, The Scripps Research Institute, La Jolla, California, USA

    Darren M Hutt, Monica A Chalfant & William E Balch

  5. Proteostasis Therapeutics Inc., Cambridge, Massachusetts, USA

    Shilpi Khanna, Bradley D Tait & Dan Garza

Authors
  1. Barbara Calamini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria Catarina Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Franck Madoux
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Darren M Hutt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shilpi Khanna
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Monica A Chalfant
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S Adrian Saldanha
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Peter Hodder
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Bradley D Tait
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Dan Garza
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. William E Balch
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Richard I Morimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

B.C. and R.I.M. designed the research plan. B.C., M.C.S., F.M., M.A.C., D.M.H., S.K. and S.A.S. designed and performed the research. B.C., M.C.S., F.M., D.M.H., S.A.S., P.H., B.D.T., D.G., W.E.B. and R.I.M. analyzed and interpreted the data. B.C. and R.I.M. wrote the manuscript. All authors reviewed the manuscript.

Corresponding author

Correspondence to Richard I Morimoto.

Ethics declarations

Competing interests

B.D.T., D.G. and S.K. are employees of Proteostasis Therapeutics Inc. (Cambridge, MA) that is developing small molecule therapeutics for protein misfolding diseases. W.E.B. is a co-founder, shareholder and a paid consultant for Proteostasis Therapeutics Inc. R.I.M. is founder, shareholder, and paid consultant for Proteostasis Therapeutics Inc.

Supplementary information

Supplementary Text and Figures

Supplementary Scheme 1, Supplementary Figures 1–13, Supplementary Tables 1–3 and Supplementary Methods (PDF 6321 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Calamini, B., Silva, M., Madoux, F. et al. Small-molecule proteostasis regulators for protein conformational diseases. Nat Chem Biol 8, 185–196 (2012). https://doi.org/10.1038/nchembio.763

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchembio.763

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