Cytoplasmic protein misfolding titrates Hsp70 to activate nuclear Hsf1
Hsf1 is an ancient transcription factor that responds to protein folding stress by inducing the heat-shock response (HSR) that restore perturbed proteostasis. Hsp70 chaperones negatively regulate the activity of Hsf1 via stress-responsive mechanisms that are poorly understood. Here, we have reconsti...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2019-09-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/47791 |
| _version_ | 1811199574805577728 |
|---|---|
| author | Anna E Masser Wenjing Kang Joydeep Roy Jayasankar Mohanakrishnan Kaimal Jany Quintana-Cordero Marc R Friedländer Claes Andréasson |
| author_facet | Anna E Masser Wenjing Kang Joydeep Roy Jayasankar Mohanakrishnan Kaimal Jany Quintana-Cordero Marc R Friedländer Claes Andréasson |
| author_sort | Anna E Masser |
| collection | DOAJ |
| description | Hsf1 is an ancient transcription factor that responds to protein folding stress by inducing the heat-shock response (HSR) that restore perturbed proteostasis. Hsp70 chaperones negatively regulate the activity of Hsf1 via stress-responsive mechanisms that are poorly understood. Here, we have reconstituted budding yeast Hsf1-Hsp70 activation complexes and find that surplus Hsp70 inhibits Hsf1 DNA-binding activity. Hsp70 binds Hsf1 via its canonical substrate binding domain and Hsp70 regulates Hsf1 DNA-binding activity. During heat shock, Hsp70 is out-titrated by misfolded proteins derived from ongoing translation in the cytosol. Pushing the boundaries of the regulatory system unveils a genetic hyperstress program that is triggered by proteostasis collapse and involves an enlarged Hsf1 regulon. The findings demonstrate how an apparently simple chaperone-titration mechanism produces diversified transcriptional output in response to distinct stress loads. |
| first_indexed | 2024-04-12T01:49:51Z |
| format | Article |
| id | doaj.art-da724e3aabc248c09d454e29b0a18d68 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T01:49:51Z |
| publishDate | 2019-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-da724e3aabc248c09d454e29b0a18d682022-12-22T03:52:58ZengeLife Sciences Publications LtdeLife2050-084X2019-09-01810.7554/eLife.47791Cytoplasmic protein misfolding titrates Hsp70 to activate nuclear Hsf1Anna E Masser0Wenjing Kang1Joydeep Roy2Jayasankar Mohanakrishnan Kaimal3Jany Quintana-Cordero4Marc R Friedländer5Claes Andréasson6https://orcid.org/0000-0001-8948-0685Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, SwedenDepartment of Molecular Biosciences, The Wenner-Gren Institute, Science for Life Laboratory, Stockholm University, Stockholm, SwedenDepartment of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, SwedenDepartment of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, SwedenDepartment of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, SwedenDepartment of Molecular Biosciences, The Wenner-Gren Institute, Science for Life Laboratory, Stockholm University, Stockholm, SwedenDepartment of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, SwedenHsf1 is an ancient transcription factor that responds to protein folding stress by inducing the heat-shock response (HSR) that restore perturbed proteostasis. Hsp70 chaperones negatively regulate the activity of Hsf1 via stress-responsive mechanisms that are poorly understood. Here, we have reconstituted budding yeast Hsf1-Hsp70 activation complexes and find that surplus Hsp70 inhibits Hsf1 DNA-binding activity. Hsp70 binds Hsf1 via its canonical substrate binding domain and Hsp70 regulates Hsf1 DNA-binding activity. During heat shock, Hsp70 is out-titrated by misfolded proteins derived from ongoing translation in the cytosol. Pushing the boundaries of the regulatory system unveils a genetic hyperstress program that is triggered by proteostasis collapse and involves an enlarged Hsf1 regulon. The findings demonstrate how an apparently simple chaperone-titration mechanism produces diversified transcriptional output in response to distinct stress loads.https://elifesciences.org/articles/47791Hsf1heat shock responseheat shock proteinHsp70chaperone |
| spellingShingle | Anna E Masser Wenjing Kang Joydeep Roy Jayasankar Mohanakrishnan Kaimal Jany Quintana-Cordero Marc R Friedländer Claes Andréasson Cytoplasmic protein misfolding titrates Hsp70 to activate nuclear Hsf1 eLife Hsf1 heat shock response heat shock protein Hsp70 chaperone |
| title | Cytoplasmic protein misfolding titrates Hsp70 to activate nuclear Hsf1 |
| title_full | Cytoplasmic protein misfolding titrates Hsp70 to activate nuclear Hsf1 |
| title_fullStr | Cytoplasmic protein misfolding titrates Hsp70 to activate nuclear Hsf1 |
| title_full_unstemmed | Cytoplasmic protein misfolding titrates Hsp70 to activate nuclear Hsf1 |
| title_short | Cytoplasmic protein misfolding titrates Hsp70 to activate nuclear Hsf1 |
| title_sort | cytoplasmic protein misfolding titrates hsp70 to activate nuclear hsf1 |
| topic | Hsf1 heat shock response heat shock protein Hsp70 chaperone |
| url | https://elifesciences.org/articles/47791 |
| work_keys_str_mv | AT annaemasser cytoplasmicproteinmisfoldingtitrateshsp70toactivatenuclearhsf1 AT wenjingkang cytoplasmicproteinmisfoldingtitrateshsp70toactivatenuclearhsf1 AT joydeeproy cytoplasmicproteinmisfoldingtitrateshsp70toactivatenuclearhsf1 AT jayasankarmohanakrishnankaimal cytoplasmicproteinmisfoldingtitrateshsp70toactivatenuclearhsf1 AT janyquintanacordero cytoplasmicproteinmisfoldingtitrateshsp70toactivatenuclearhsf1 AT marcrfriedlander cytoplasmicproteinmisfoldingtitrateshsp70toactivatenuclearhsf1 AT claesandreasson cytoplasmicproteinmisfoldingtitrateshsp70toactivatenuclearhsf1 |