Nat. Commun.: co-auth.: PAF

Nat. Commun. 2020 Nov 25;11(1):5975. doi: 10.1038/s41467-020-19783-w.

The Hsp70-Hsp90 co-chaperone Hop/Stip1 shifts the proteostatic balance from folding towards degradation

Kaushik Bhattacharya 1Lorenz Weidenauer 2Tania Morán Luengo 3 4Ellis C Pieters 3 4Pablo C Echeverría 1 5Lilia Bernasconi 1Diana Wider 1Yashar Sadian 6Margreet B Koopman 3 4Matthieu Villemin 1Christoph Bauer 6Stefan G D Rüdiger 3 4Manfredo Quadroni 2Didier Picard 7

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Hop/Stip1/Sti1 is thought to be essential as a co-chaperone to facilitate substrate transfer between the Hsp70 and Hsp90 molecular chaperones. Despite this proposed key function for protein folding and maturation, it is not essential in a number of eukaryotes and bacteria lack an ortholog. We set out to identify and to characterize its eukaryote-specific function. Human cell lines and the budding yeast with deletions of the Hop/Sti1 gene display reduced proteasome activity due to inefficient capping of the core particle with regulatory particles. Unexpectedly, knock-out cells are more proficient at preventing protein aggregation and at promoting protein refolding. Without the restraint by Hop, a more efficient folding activity of the prokaryote-like Hsp70-Hsp90 complex, which can also be demonstrated in vitro, compensates for the proteasomal defect and ensures the proteostatic equilibrium. Thus, cells may act on the level and/or activity of Hop to shift the proteostatic balance between folding and degradation.