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Differential role of cytosolic Hsp70s in longevity assurance and protein quality control

View ORCID ProfileRebecca Andersson, View ORCID ProfileAnna Maria Eisele-Bürger, View ORCID ProfileSarah Hanzén, View ORCID ProfileKatarina Vielfort, View ORCID ProfileDavid Öling, View ORCID ProfileFrederik Eisele, View ORCID ProfileGustav Johansson, View ORCID ProfileTobias Gustafsson, View ORCID ProfileKristian Kvint, View ORCID ProfileThomas Nyström
doi: https://doi.org/10.1101/2020.06.25.170670
Rebecca Andersson
1Department of microbiology and immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 403 50 Gothenburg, Sweden
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Anna Maria Eisele-Bürger
1Department of microbiology and immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 403 50 Gothenburg, Sweden
2Department of chemistry and molecular biology, Faculty of Science, University of Gothenburg, 403 50 Gothenburg, Sweden
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Sarah Hanzén
1Department of microbiology and immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 403 50 Gothenburg, Sweden
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Katarina Vielfort
1Department of microbiology and immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 403 50 Gothenburg, Sweden
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David Öling
2Department of chemistry and molecular biology, Faculty of Science, University of Gothenburg, 403 50 Gothenburg, Sweden
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Frederik Eisele
1Department of microbiology and immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 403 50 Gothenburg, Sweden
2Department of chemistry and molecular biology, Faculty of Science, University of Gothenburg, 403 50 Gothenburg, Sweden
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Gustav Johansson
2Department of chemistry and molecular biology, Faculty of Science, University of Gothenburg, 403 50 Gothenburg, Sweden
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Tobias Gustafsson
2Department of chemistry and molecular biology, Faculty of Science, University of Gothenburg, 403 50 Gothenburg, Sweden
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Kristian Kvint
2Department of chemistry and molecular biology, Faculty of Science, University of Gothenburg, 403 50 Gothenburg, Sweden
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Thomas Nyström
1Department of microbiology and immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 403 50 Gothenburg, Sweden
2Department of chemistry and molecular biology, Faculty of Science, University of Gothenburg, 403 50 Gothenburg, Sweden
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  • For correspondence: thomas.nystrom@cmb.gu.se
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ABSTRACT

70 kDa heat shock proteins (Hsp70) are essential chaperones of the protein quality control network; vital for cellular fitness and longevity. The four cytosolic Hsp70’s in yeast, Ssa1-4, are thought to be functionally redundant but the absence of Ssa1 and Ssa2 causes a severe reduction in cellular reproduction and accelerates replicative aging. In our efforts to identify which Hsp70 activities are most important for longevity assurance, we systematically investigated the capacity of Ssa4 to carry out the different activities performed by Ssa1/2 by overproducing Ssa4 in cells lacking these Hsp70 chaperones. We found that Ssa4, when overproduced in cells lacking Ssa1/2, rescued growth, mitigated aggregate formation, restored spatial deposition of aggregates into protein inclusions, and promoted protein degradation. In contrast, Ssa4 overproduction in the Hsp70 deficient cells failed to restore the recruitment of the disaggregase Hsp104 to misfolded/aggregated proteins, to fully restore clearance of protein aggregates, and to bring back the formation of the nucleolus-associated aggregation compartment. Exchanging the nucleotide-binding domain of Ssa4 with that of Ssa1 suppressed this ‘defect’ of Ssa4. Interestingly, Ssa4 overproduction extended the short lifespan of ssa1Δ ssa2Δ mutant cells to a lifespan comparable to, or even longer than, wild type cells, demonstrating that Hsp104-dependent aggregate clearance is not a prerequisite for longevity assurance in yeast.

AUTHOR SUMMARY All organisms have proteins that network together to stabilize and protect the cell throughout its lifetime. One of these types of proteins are the Hsp70s (heat shock protein 70). Hsp70 proteins take part in folding other proteins to their functional form, untangling proteins from aggregates, organize aggregates inside the cell and ensure that damaged proteins are destroyed. In this study, we investigated three closely related Hsp70 proteins in yeast; Ssa1, 2 and 4, in an effort to describe the functional difference of Ssa4 compared to Ssa1 and 2 and to answer the question: What types of cellular stress protection are necessary to reach a normal lifespan? We show that Ssa4 can perform many of the same tasks as Ssa1 and 2, but Ssa4 doesn’t interact in the same manner as Ssa1 and 2 with other types of proteins. This leads to a delay in removing protein aggregates created after heat stress. Ssa4 also cannot ensure that misfolded proteins aggregate correctly inside the nucleus of the cell. However, this turns out not to be necessary for yeast cells to achieve a full lifespan, which shows us that as long as cells can prevent aggregates from forming in the first place, they can reach a full lifespan.

Competing Interest Statement

D. Ö. is employed by AstraZeneca Mölndal, Sweden F.E. is employed by AstraZeneca Mölndal, Sweden S.H. is employed by Cochlear Nordic AB, Mölnlycke, Sweden

Footnotes

  • Updated with supplemental data and author ORCID id's.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 29, 2020.
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Differential role of cytosolic Hsp70s in longevity assurance and protein quality control
Rebecca Andersson, Anna Maria Eisele-Bürger, Sarah Hanzén, Katarina Vielfort, David Öling, Frederik Eisele, Gustav Johansson, Tobias Gustafsson, Kristian Kvint, Thomas Nyström
bioRxiv 2020.06.25.170670; doi: https://doi.org/10.1101/2020.06.25.170670
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Differential role of cytosolic Hsp70s in longevity assurance and protein quality control
Rebecca Andersson, Anna Maria Eisele-Bürger, Sarah Hanzén, Katarina Vielfort, David Öling, Frederik Eisele, Gustav Johansson, Tobias Gustafsson, Kristian Kvint, Thomas Nyström
bioRxiv 2020.06.25.170670; doi: https://doi.org/10.1101/2020.06.25.170670

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