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@ARTICLE{Jawed:212413,
      author       = {A. Jawed and C.-T. Ho and T. Grousl and A. Shrivastava and
                      T. Ruppert and B. Bukau$^*$ and A. Mogk},
      title        = {{B}alanced activities of {H}sp70 and the ubiquitin
                      proteasome system underlie cellular protein homeostasis.},
      journal      = {Frontiers in molecular biosciences},
      volume       = {9},
      issn         = {2296-889X},
      address      = {Lausanne},
      publisher    = {Frontiers},
      reportid     = {DKFZ-2023-00132},
      pages        = {1106477},
      year         = {2023},
      note         = {#LA:A250#},
      abstract     = {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 (fes1Δ
                      hsp104Δ, ΔΔ) and suffering from low Hsp70 capacity.
                      Growth of ΔΔbtn2Δ 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
                      ΔΔbtn2Δ cells, which are affected in two major protein
                      quality control branches. We show that ΔΔbtn2Δ 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 ΔΔbtn2Δ 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.},
      keywords     = {26S proteasome (Other) / Hsp70 (Other) / chaperone (Other)
                      / protein quality control (Other) / protein sequestration
                      (Other)},
      cin          = {A250},
      ddc          = {570},
      cid          = {I:(DE-He78)A250-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36660429},
      pmc          = {pmc:PMC9845930},
      doi          = {10.3389/fmolb.2022.1106477},
      url          = {https://inrepo02.dkfz.de/record/212413},
}