title: CBP/p300 Bromodomains Regulate Amyloid-like Protein Aggregation upon Aberrant Lysine Acetylation.
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.
authors.affiliation: Department of Oncology, University of Oxford, Old Road Campus Research Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Heidi
authors.initials: H
authors.lastname: Olzscha
authors.affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Oleg
authors.initials: O
authors.lastname: Fedorov
authors.affiliation: Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Roosevelt Drive, Oxford OX3 7FZ, UK.
authors.forename: Benedikt M
authors.initials: BM
authors.lastname: Kessler
authors.affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.affiliation: 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.
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: La Thangue
mesh_terms: D000107:Acetylation; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D000071058:Huntingtin Protein / Q000737:chemistry / Q000378:metabolism; D008239:Lysine / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000682:Amyloid; D000071058:Huntingtin Protein; D066329:Protein Aggregates; D050880:p300-CBP Transcription Factors; D046988:Proteasome Endopeptidase Complex; D008239:Lysine
keywords: CBP; acetylation; aggregation; amyloid; bromodomain; histone deacetylase; huntingtin; inhibitor; p300; proteostasis