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

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

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Gene Knockout Techniques
  • HCT116 Cells
  • HEK293 Cells
  • HSP70 Heat-Shock Proteins / metabolism*
  • HSP90 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / metabolism*
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Mutagenesis, Site-Directed
  • Mutation
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Aggregates
  • Protein Folding
  • Proteolysis
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*

Substances

  • HSP70 Heat-Shock Proteins
  • HSP90 Heat-Shock Proteins
  • Heat-Shock Proteins
  • Protein Aggregates
  • STI1 protein, S cerevisiae
  • STIP1 protein, human
  • Saccharomyces cerevisiae Proteins
  • Proteasome Endopeptidase Complex