Nuclear Hsp104 safeguards the dormant translation machinery during quiescence

• Published in: Nature communications Vol. 15; no. 1; pp. 315 - 20
• Main Authors: Kohler, Verena, Kohler, Andreas, Berglund, Lisa Larsson, Hao, Xinxin, Gersing, Sarah, Imhof, Axel, Nyström, Thomas, Höög, Johanna L., Ott, Martin, Andréasson, Claes, Büttner, Sabrina
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.01.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 14; 14/19; 14/28; 42/35; 45/47; 631/337/574; 631/45/470/2284; 631/80/470/2284; 631/80/642/1363; 82/58; 96/63; Aging; Biosynthesis; Cell and Molecular Biology; Cell Cycle; Cell Division; Cell viability; Cell- och molekylärbiologi; Cytosol; Heat-Shock Proteins - metabolism; Humanities and Social Sciences; Initiation factor eIF-2; Metabolism; multidisciplinary; Nuclei (cytology); Nutrients; Protein Aggregates; Protein Biosynthesis; Protein folding; Protein interaction; Protein synthesis; Proteins; Proteomes; Quality control; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - metabolism; Science; Science (multidisciplinary); Yeast
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-44538-8

The resilience of cellular proteostasis declines with age, which drives protein aggregation and compromises viability. The nucleus has emerged as a key quality control compartment that handles misfolded proteins produced by the cytosolic protein biosynthesis system. Here, we find that age-associated metabolic cues target the yeast protein disaggregase Hsp104 to the nucleus to maintain a functional nuclear proteome during quiescence. The switch to respiratory metabolism and the accompanying decrease in translation rates direct cytosolic Hsp104 to the nucleus to interact with latent translation initiation factor eIF2 and to suppress protein aggregation. Hindering Hsp104 from entering the nucleus in quiescent cells results in delayed re-entry into the cell cycle due to compromised resumption of protein synthesis. In sum, we report that cytosolic-nuclear partitioning of the Hsp104 disaggregase is a critical mechanism to protect the latent protein synthesis machinery during quiescence in yeast, ensuring the rapid restart of translation once nutrients are replenished. During aging, proteins are damaged and can misfold, compromising cellular viability. Here, Kohler et al. uncover how aging cells maintain fitness by redirecting the protein repair factor Hsp104 to the nucleus in response to metabolic cues.