Sis1 potentiates the stress response to protein aggregation and elevated temperature

• Published in: Nature communications Vol. 11; no. 1; pp. 6271 - 16
• Main Authors: Klaips, Courtney L., Gropp, Michael H. M., Hipp, Mark S., Hartl, F. Ulrich
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08-12-2020; Nature Publishing Group; Nature Portfolio
• Subjects: 14/19; 49/91; 631/45; 631/45/470/1981; 631/45/470/2284; Agglomeration; Amyloid; Cellular stress response; DNA-Binding Proteins - metabolism; Environmental changes; Gene Knockout Techniques; Genetic screening; Heat stress; Heat tolerance; Heat-Shock Proteins - metabolism; Heat-Shock Response; HEK293 Cells; High temperature; Homology; HSF1 protein; HSP40 Heat-Shock Proteins - genetics; HSP40 Heat-Shock Proteins - metabolism; Hsp40 protein; Hsp70 protein; Humanities and Social Sciences; Humans; Huntingtin; Hypersensitivity; Inclusions; Mammalian cells; Mammals; Molecular Chaperones - genetics; Molecular Chaperones - metabolism; multidisciplinary; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Oligomers; Peptides - metabolism; Polyglutamine; Protein Aggregates; Protein Folding; Protein interaction; Proteins; Saccharomyces cerevisiae - physiology; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Science; Science (multidisciplinary); Transcription Factors - metabolism; Trinucleotide repeat diseases; Yeast; Yeasts
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-20000-x

Cells adapt to conditions that compromise protein conformational stability by activating various stress response pathways, but the mechanisms used in sensing misfolded proteins remain unclear. Moreover, aggregates of disease proteins often fail to induce a productive stress response. Here, using a yeast model of polyQ protein aggregation, we identified Sis1, an essential Hsp40 co-chaperone of Hsp70, as a critical sensor of proteotoxic stress. At elevated levels, Sis1 prevented the formation of dense polyQ inclusions and directed soluble polyQ oligomers towards the formation of permeable condensates. Hsp70 accumulated in a liquid-like state within this polyQ meshwork, resulting in a potent activation of the HSF1 dependent stress response. Sis1, and the homologous DnaJB6 in mammalian cells, also regulated the magnitude of the cellular heat stress response, suggesting a general role in sensing protein misfolding. Sis1/DnaJB6 functions as a limiting regulator to enable a dynamic stress response and avoid hypersensitivity to environmental changes.
Identifying factors that enable cells to induce a potent stress response to amyloid-like aggregation can provide further insight into the mechanism of stress regulation. Here, the authors express polyglutamine-expanded Huntingtin as a model disease protein in yeast cells and perform a genetic screen for chaperone factors that allow yeast cells to activate a potent stress response. They identify Sis1, an essential Hsp40 co-chaperone of Hsp70, as a critical sensor of proteotoxic stress and further show that both Sis1 and its mammalian homolog DnaJB6 regulate the magnitude of the cellular heat stress response, indicating that this mechanism is conserved.