Transportable, Chemical Genetic Methodology for the Small Molecule-Mediated Inhibition of Heat Shock Factor 1
Proteostasis in the cytosol is governed by the heat shock response. The master regulator of the heat shock response, heat shock factor 1 (HSF1), and key chaperones whose levels are HSF1-regulated have emerged as high-profile targets for therapeutic applications ranging from protein misfolding-relate...
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| Format: | Article |
| Language: | en_US |
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American Chemical Society
2017
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| Online Access: | http://hdl.handle.net/1721.1/106953 https://orcid.org/0000-0001-9986-9037 https://orcid.org/0000-0001-7104-0278 https://orcid.org/0000-0002-6511-3431 |
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| author | Moore, Christopher Lawrence Dewal, Mahender Nekongo, Emmanuel E Santiago, Sebasthian Lu, Nancy B. Levine, Stuart S. Shoulders, Matthew D. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Moore, Christopher Lawrence Dewal, Mahender Nekongo, Emmanuel E Santiago, Sebasthian Lu, Nancy B. Levine, Stuart S. Shoulders, Matthew D. |
| author_sort | Moore, Christopher Lawrence |
| collection | MIT |
| description | Proteostasis in the cytosol is governed by the heat shock response. The master regulator of the heat shock response, heat shock factor 1 (HSF1), and key chaperones whose levels are HSF1-regulated have emerged as high-profile targets for therapeutic applications ranging from protein misfolding-related disorders to cancer. Nonetheless, a generally applicable methodology to selectively and potently inhibit endogenous HSF1 in a small molecule-dependent manner in disease model systems remains elusive. Also problematic, the administration of even highly selective chaperone inhibitors often has the side effect of activating HSF1 and thereby inducing a compensatory heat shock response. Herein, we report a ligand-regulatable, dominant negative version of HSF1 that addresses these issues. Our approach, which required engineering a new dominant negative HSF1 variant, permits dosable inhibition of endogenous HSF1 with a selective small molecule in cell-based model systems of interest. The methodology allows us to uncouple the pleiotropic effects of chaperone inhibitors and environmental toxins from the concomitantly induced compensatory heat shock response. Integration of our method with techniques to activate HSF1 enables the creation of cell lines in which the cytosolic proteostasis network can be up- or down-regulated by orthogonal small molecules. Selective, small molecule-mediated inhibition of HSF1 has distinctive implications for the proteostasis of both chaperone-dependent globular proteins and aggregation-prone intrinsically disordered proteins. Altogether, this work provides critical methods for continued exploration of the biological roles of HSF1 and the therapeutic potential of heat shock response modulation. |
| first_indexed | 2024-09-23T10:36:42Z |
| format | Article |
| id | mit-1721.1/106953 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:36:42Z |
| publishDate | 2017 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | mit-1721.1/1069532022-09-30T21:47:48Z Transportable, Chemical Genetic Methodology for the Small Molecule-Mediated Inhibition of Heat Shock Factor 1 Moore, Christopher Lawrence Dewal, Mahender Nekongo, Emmanuel E Santiago, Sebasthian Lu, Nancy B. Levine, Stuart S. Shoulders, Matthew D. Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Chemistry Moore, Christopher Lawrence Dewal, Mahender Nekongo, Emmanuel E Santiago, Sebasthian Lu, Nancy B. Levine, Stuart S. Shoulders, Matthew D. Proteostasis in the cytosol is governed by the heat shock response. The master regulator of the heat shock response, heat shock factor 1 (HSF1), and key chaperones whose levels are HSF1-regulated have emerged as high-profile targets for therapeutic applications ranging from protein misfolding-related disorders to cancer. Nonetheless, a generally applicable methodology to selectively and potently inhibit endogenous HSF1 in a small molecule-dependent manner in disease model systems remains elusive. Also problematic, the administration of even highly selective chaperone inhibitors often has the side effect of activating HSF1 and thereby inducing a compensatory heat shock response. Herein, we report a ligand-regulatable, dominant negative version of HSF1 that addresses these issues. Our approach, which required engineering a new dominant negative HSF1 variant, permits dosable inhibition of endogenous HSF1 with a selective small molecule in cell-based model systems of interest. The methodology allows us to uncouple the pleiotropic effects of chaperone inhibitors and environmental toxins from the concomitantly induced compensatory heat shock response. Integration of our method with techniques to activate HSF1 enables the creation of cell lines in which the cytosolic proteostasis network can be up- or down-regulated by orthogonal small molecules. Selective, small molecule-mediated inhibition of HSF1 has distinctive implications for the proteostasis of both chaperone-dependent globular proteins and aggregation-prone intrinsically disordered proteins. Altogether, this work provides critical methods for continued exploration of the biological roles of HSF1 and the therapeutic potential of heat shock response modulation. Edward Mallinckrodt, Jr. Foundation (Faculty Scholar Award) Smith Family Foundation (Excellence in Biomedical Research Award) National Institutes of Health (U.S.) (Grants 1DP2GM119162 and P30-ES002109) Massachusetts Institute of Technology. Dept. of Chemistry National Science Foundation (U.S.) (Graduate Research Fellowship) United Negro College Fund (Merck Postdoctoral Fellowship) 2017-02-16T15:15:00Z 2017-02-16T15:15:00Z 2015-10 2015-09 Article http://purl.org/eprint/type/JournalArticle 1554-8929 1554-8937 http://hdl.handle.net/1721.1/106953 Moore, Christopher L. et al. “Transportable, Chemical Genetic Methodology for the Small Molecule-Mediated Inhibition of Heat Shock Factor 1.” ACS Chemical Biology 11.1 (2016): 200–210. https://orcid.org/0000-0001-9986-9037 https://orcid.org/0000-0001-7104-0278 https://orcid.org/0000-0002-6511-3431 en_US http://dx.doi.org/10.1021/acschembio.5b00740 ACS Chemical Biology Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Chemical Society PMC |
| spellingShingle | Moore, Christopher Lawrence Dewal, Mahender Nekongo, Emmanuel E Santiago, Sebasthian Lu, Nancy B. Levine, Stuart S. Shoulders, Matthew D. Transportable, Chemical Genetic Methodology for the Small Molecule-Mediated Inhibition of Heat Shock Factor 1 |
| title | Transportable, Chemical Genetic Methodology for the Small Molecule-Mediated Inhibition of Heat Shock Factor 1 |
| title_full | Transportable, Chemical Genetic Methodology for the Small Molecule-Mediated Inhibition of Heat Shock Factor 1 |
| title_fullStr | Transportable, Chemical Genetic Methodology for the Small Molecule-Mediated Inhibition of Heat Shock Factor 1 |
| title_full_unstemmed | Transportable, Chemical Genetic Methodology for the Small Molecule-Mediated Inhibition of Heat Shock Factor 1 |
| title_short | Transportable, Chemical Genetic Methodology for the Small Molecule-Mediated Inhibition of Heat Shock Factor 1 |
| title_sort | transportable chemical genetic methodology for the small molecule mediated inhibition of heat shock factor 1 |
| url | http://hdl.handle.net/1721.1/106953 https://orcid.org/0000-0001-9986-9037 https://orcid.org/0000-0001-7104-0278 https://orcid.org/0000-0002-6511-3431 |
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