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Cell. 2014 Feb 27;156(5):975-85. doi: 10.1016/j.cell.2014.01.055.

Interplay of acetyltransferase EP300 and the proteasome system in regulating heat shock transcription factor 1.

Author information

1
Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
2
Medical Systems Biology, University Hospital and Medical Faculty, Carl Gustav Carus University of Technology, Fetscherstrasse 74, 01307 Dresden, Germany.
3
Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany. Electronic address: uhartl@biochem.mpg.de.

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.

PMID:
24581496
DOI:
10.1016/j.cell.2014.01.055
[Indexed for MEDLINE]
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