Artificial Hsp104-mediated systems for re-localizing protein aggregates

Arthur Fischbach (), Angela Johns, Kara L. Schneider, Xinxin Hao, Peter Tessarz and Thomas Nyström ()
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Arthur Fischbach: University of Gothenburg
Angela Johns: University of Gothenburg
Kara L. Schneider: University of Gothenburg
Xinxin Hao: University of Gothenburg
Peter Tessarz: Max Planck Institute for Biology of Ageing
Thomas Nyström: University of Gothenburg

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Spatial Protein Quality Control (sPQC) sequesters misfolded proteins into specific, organelle-associated inclusions within the cell to control their toxicity. To approach the role of sPQC in cellular fitness, neurodegenerative diseases and aging, we report on the construction of Hsp100-based systems in budding yeast cells, which can artificially target protein aggregates to non-canonical locations. We demonstrate that aggregates of mutant huntingtin (mHtt), the disease-causing agent of Huntington’s disease can be artificially targeted to daughter cells as well as to eisosomes and endosomes with this approach. We find that the artificial removal of mHtt inclusions from mother cells protects them from cell death suggesting that even large mHtt inclusions may be cytotoxic, a trait that has been widely debated. In contrast, removing inclusions of endogenous age-associated misfolded proteins does not significantly affect the lifespan of mother cells. We demonstrate also that this approach is able to manipulate mHtt inclusion formation in human cells and has the potential to be useful as an alternative, complementary approach to study the role of sPQC, for example in aging and neurodegenerative disease.

Date: 2023
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DOI: 10.1038/s41467-023-37706-3

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