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Cell Chem Biol. 2017 Jan 19;24(1):9-23. doi: 10.1016/j.chembiol.2016.11.009. Epub 2016 Dec 15.

CBP/p300 Bromodomains Regulate Amyloid-like Protein Aggregation upon Aberrant Lysine Acetylation.

Author information

1
Department of Oncology, University of Oxford, Old Road Campus Research Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK.
2
Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK.
3
Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Roosevelt Drive, Oxford OX3 7FZ, UK.
4
Department of Oncology, University of Oxford, Old Road Campus Research Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK. Electronic address: nick.lathangue@oncology.ox.ac.uk.

Abstract

Lysine acetylation is becoming increasingly recognized as a general biological principle in cellular homeostasis, and is subject to abnormal control in different human pathologies. Here, we describe a global effect on amyloid-like protein aggregation in human cells that results from aberrant lysine acetylation. Bromodomain reader proteins are involved in the aggregation process and, using chemical biology and gene silencing, we establish that p300/CBP bromodomains are necessary for aggregation to occur. Moreover, protein aggregation disturbs proteostasis by impairing the ubiquitin proteasome system (UPS) and protein translation, resulting in decreased cell viability. p300/CBP bromodomain inhibitors impede aggregation, which coincides with enhanced UPS function and increased cell viability. Aggregation of a pathologically relevant form of huntingtin protein is similarly affected by p300/CBP inhibition. Our results have implications for understanding the molecular basis of protein aggregation, and highlight the possibility of treating amyloid-like pathologies and related protein folding diseases with bromodomain inhibitor-based strategies.

KEYWORDS:

CBP; acetylation; aggregation; amyloid; bromodomain; histone deacetylase; huntingtin; inhibitor; p300; proteostasis

Comment in

PMID:
27989401
PMCID:
PMC5266481
DOI:
10.1016/j.chembiol.2016.11.009
[Indexed for MEDLINE]
Free PMC Article

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