title: UBL/BAG-domain co-chaperones cause cellular stress upon overexpression through constitutive activation of Hsf1.
abstract: As a result of exposure to stress conditions, mutations, or defects during synthesis, cellular proteins are prone to misfold. To cope with such partially denatured proteins, cells mount a regulated transcriptional response involving the Hsf1 transcription factor, which drives the synthesis of molecular chaperones and other stress-relieving proteins. Here, we show that the fission yeast Schizosaccharomyces pombe orthologues of human BAG-1, Bag101, and Bag102, are Hsp70 co-chaperones that associate with 26S proteasomes. Only a subgroup of Hsp70-type chaperones, including Ssa1, Ssa2, and Sks2, binds Bag101 and Bag102 and key residues in the Hsp70 ATPase domains, required for interaction with Bag101 and Bag102, were identified. In humans, BAG-1 overexpression is typically observed in cancers. Overexpression of bag101 and bag102 in fission yeast leads to a strong growth defect caused by triggering Hsp70 to release and activate the Hsf1 transcription factor. Accordingly, the bag101-linked growth defect is alleviated in strains containing a reduced amount of Hsf1 but aggravated in hsp70 deletion strains. In conclusion, we propose that the fission yeast UBL/BAG proteins release Hsf1 from Hsp70, leading to constitutive Hsf1 activation and growth defects.
authors.affiliation: The Linderstrøm-Land Centre, Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen N, Denmark.
authors.forename: Esben G
authors.initials: EG
authors.lastname: Poulsen
authors.affiliation: The Linderstrøm-Land Centre, Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen N, Denmark.
authors.forename: Caroline
authors.initials: C
authors.lastname: Kampmeyer
authors.affiliation: The Linderstrøm-Land Centre, Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen N, Denmark.
authors.forename: Franziska
authors.initials: F
authors.lastname: Kriegenburg
authors.affiliation: Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen N, Denmark.
authors.forename: Jens V
authors.initials: JV
authors.lastname: Johansen
authors.affiliation: Institute for Genetics, University of Cologne, 50674, Cologne, Germany.
authors.forename: Kay
authors.initials: K
authors.lastname: Hofmann
authors.affiliation: The Linderstrøm-Land Centre, Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen N, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Holmberg
authors.affiliation: The Linderstrøm-Land Centre, Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen N, Denmark. rhpetersen@bio.ku.dk.
authors.forename: Rasmus
authors.identifier: 0000-0002-4155-7791
authors.initials: R
authors.lastname: Hartmann-Petersen
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D017930:Genes, Reporter; D000076249:Heat Shock Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018869:Heat-Shock Response; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D025341:Principal Component Analysis; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012568:Schizosaccharomyces / Q000254:growth & development / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism*; D013696:Temperature; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C091732:BCL2-associated athanogene 1 protein; D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; D018832:Molecular Chaperones; D029702:Schizosaccharomyces pombe Proteins; D014157:Transcription Factors; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease
keywords: Chaperone; Heat shock; Proteasome; Protein folding; Stress; Ubiquitin