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Translational reprogramming in response to accumulating stressors ensures critical threshold levels of Hsp90 for mammalian life

Kaushik Bhattacharya, Samarpan Maiti, Szabolcs Zahoran, Lorenz Weidenauer, Dina Hany, Diana Wider, Lilia Bernasconi, Manfredo Quadroni, Martine Collart, View ORCID ProfileDidier Picard
doi: https://doi.org/10.1101/2022.02.11.480086
Kaushik Bhattacharya
1Department of Molecular and Cellular Biology, University of Geneva, Geneva, Switzerland
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Samarpan Maiti
1Department of Molecular and Cellular Biology, University of Geneva, Geneva, Switzerland
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Szabolcs Zahoran
2Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland
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Lorenz Weidenauer
3Protein Analysis Facility, Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
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Dina Hany
1Department of Molecular and Cellular Biology, University of Geneva, Geneva, Switzerland
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Diana Wider
1Department of Molecular and Cellular Biology, University of Geneva, Geneva, Switzerland
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Lilia Bernasconi
1Department of Molecular and Cellular Biology, University of Geneva, Geneva, Switzerland
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Manfredo Quadroni
3Protein Analysis Facility, Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
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Martine Collart
2Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland
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Didier Picard
1Department of Molecular and Cellular Biology, University of Geneva, Geneva, Switzerland
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  • ORCID record for Didier Picard
  • For correspondence: didier.picard@unige.ch
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Abstract

The cytosolic molecular chaperone Hsp90 is essential for eukaryotic life1, 2. It is involved in multiple branches of proteostasis2, 3, and as a molecular capacitor in morphological evolution4. Although reduced Hsp90 levels cause phenotypic variations5, 6 and correlate with aging7, whether eukaryotic cells and organisms can tune the basal Hsp90 protein levels to alleviate physiologically accumulated stress is unknown. To begin to explore this question, we investigated whether and how mice adapt to the deletion of three out of four alleles encoding cytosolic Hsp90, one Hsp90β allele being the only remaining one. While the vast majority of such mouse embryos die during gestation, survivors apparently manage to increase their Hsp90β protein to at least wild-type levels. Further mechanistic studies revealed an internal ribosome entry site in the 5’UTR of the Hsp90β mRNA allowing translational reprogramming to compensate for the genetic loss of Hsp90 alleles and in response to stress. We found that the minimum amount of total Hsp90 that is required to support viability of mammalian cells and organisms is 50-70% of what is normally there. Those that fail to maintain a threshold level are subject to accelerated senescence, proteostatic collapse, and ultimately death. Therefore, considering that Hsp90 levels can be reduced ≥100-fold in the unicellular budding yeast, critical threshold levels of Hsp90 have been markedly increased during eukaryotic evolution. The incompressible part of the steady-state levels of Hsp90 may have increased to accommodate the ever-growing complexity of the proteome8 on the path towards mammals.

Competing Interest Statement

The authors have declared no competing interest.

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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 4.0 International license.
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Posted February 11, 2022.
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Translational reprogramming in response to accumulating stressors ensures critical threshold levels of Hsp90 for mammalian life
Kaushik Bhattacharya, Samarpan Maiti, Szabolcs Zahoran, Lorenz Weidenauer, Dina Hany, Diana Wider, Lilia Bernasconi, Manfredo Quadroni, Martine Collart, Didier Picard
bioRxiv 2022.02.11.480086; doi: https://doi.org/10.1101/2022.02.11.480086
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Translational reprogramming in response to accumulating stressors ensures critical threshold levels of Hsp90 for mammalian life
Kaushik Bhattacharya, Samarpan Maiti, Szabolcs Zahoran, Lorenz Weidenauer, Dina Hany, Diana Wider, Lilia Bernasconi, Manfredo Quadroni, Martine Collart, Didier Picard
bioRxiv 2022.02.11.480086; doi: https://doi.org/10.1101/2022.02.11.480086

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