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Balanced activities of Hsp70 and the ubiquitin proteasome system underlie cellular protein homeostasis
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SYSNO ASEP 0579770 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Balanced activities of Hsp70 and the ubiquitin proteasome system underlie cellular protein homeostasis Author(s) Jawed, A. (DE)
Ho, C. (DE)
Groušl, Tomáš (MBU-M) RID, ORCID
Shrivastava, A. (DE)
Ruppert, T. (DE)
Bukau, B. (DE)
Mogk, A. (DE)Article number 1106477 Source Title Frontiers in molecular biosciences
Roč. 9, 4 January 2023 (2023)Number of pages 14 s. Language eng - English Country CH - Switzerland Keywords misfolded proteins ; yeast ; sequestration ; regulator ; stress ; enzyme ; hsp42 ; protein quality control ; Hsp70 ; 26S proteasome ; chaperone ; protein sequestration OECD category Microbiology Method of publishing Open access Institutional support MBU-M - RVO:61388971 UT WOS 000950629900001 EID SCOPUS 85146469891 DOI 10.3389/fmolb.2022.1106477 Annotation To counteract proteotoxic stress and cellular aging, protein quality control (PQC) systems rely on the refolding, degradation and sequestration of misfolded proteins. In Saccharomyces cerevisiae the Hsp70 chaperone system plays a central role in protein refolding, while degradation is predominantly executed by the ubiquitin proteasome system (UPS). The sequestrases Hsp42 and Btn2 deposit misfolded proteins in cytosolic and nuclear inclusions, thereby restricting the accessibility of misfolded proteins to Hsp70 and preventing the exhaustion of limited Hsp70 resources. Therefore, in yeast, sequestrase mutants show negative genetic interactions with double mutants lacking the Hsp70 co-chaperone Fes1 and the Hsp104 disaggregase (fes1 delta hsp104 delta, delta delta) and suffering from low Hsp70 capacity. Growth of delta delta btn2 delta mutants is highly temperature-sensitive and results in proteostasis breakdown at non-permissive temperatures. Here, we probed for the role of the ubiquitin proteasome system in maintaining protein homeostasis in delta delta btn2 delta cells, which are affected in two major protein quality control branches. We show that delta delta btn2 delta cells induce expression of diverse stress related pathways including the ubiquitin proteasome system to counteract the proteostasis defects. Ubiquitin proteasome system dependent degradation of the stringent Hsp70 substrate firefly Luciferase in the mutant cells mirrors such compensatory activities of the protein quality control system. Surprisingly however, the enhanced ubiquitin proteasome system activity does not improve but aggravates the growth defects of ddbtn2d cells. Reducing ubiquitin proteasome system activity in the mutant by lowering the levels of functional 26S proteasomes improved growth, increased refolding yield of the Luciferase reporter and attenuated global stress responses. Our findings indicate that an imbalance between Hsp70-dependent refolding, sequestration and ubiquitin proteasome system-mediated degradation activities strongly affects protein homeostasis of Hsp70 capacity mutants and contributes to their severe growth phenotypes. Workplace Institute of Microbiology Contact Eliška Spurná, eliska.spurna@biomed.cas.cz, Tel.: 241 062 231 Year of Publishing 2024 Electronic address https://www.frontiersin.org/articles/10.3389/fmolb.2022.1106477/full
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