title: Interplay of acetyltransferase EP300 and the proteasome system in regulating heat shock transcription factor 1.
abstract: When exposed to proteotoxic environmental conditions, mammalian cells activate the cytosolic stress response in order to restore protein homeostasis. A key feature of this response is the heat shock transcription factor 1 (HSF1)-dependent expression of molecular chaperones. Here, we describe the results of an RNA interference screen in HeLa cells to identify modulators of stress response induction and attenuation. The modulator proteins are localized in multiple cellular compartments, with chromatin modifiers and nuclear protein quality control playing a central regulatory role. We find that the acetyltransferase, EP300, controls the cellular level of activatable HSF1. This involves acetylation of HSF1 at multiple lysines not required for function and results in stabilization of HSF1 against proteasomal turnover. Acetylation of functionally critical lysines during stress serves to fine-tune HSF1 activation. Finally, the nuclear proteasome system functions in attenuating the stress response by degrading activated HSF1 in a manner linked with the clearance of misfolded proteins.
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Swasti
authors.initials: S
authors.lastname: Raychaudhuri
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Loew
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Roman
authors.initials: R
authors.lastname: Körner
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Pinkert
authors.affiliation: Medical Systems Biology, University Hospital and Medical Faculty, Carl Gustav Carus University of Technology, Fetscherstrasse 74, 01307 Dresden, Germany.
authors.forename: Mirko
authors.initials: M
authors.lastname: Theis
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Manajit
authors.initials: M
authors.lastname: Hayer-Hartl
authors.affiliation: Medical Systems Biology, University Hospital and Medical Faculty, Carl Gustav Carus University of Technology, Fetscherstrasse 74, 01307 Dresden, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Buchholz
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany. Electronic address: uhartl@biochem.mpg.de.
authors.forename: F Ulrich
authors.initials: FU
authors.lastname: Hartl
mesh_terms: D000107:Acetylation; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017510:Protein Folding; D060066:Protein Interaction Maps; D020543:Proteome / Q000032:analysis / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D020543:Proteome; D014157:Transcription Factors; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D046988:Proteasome Endopeptidase Complex