CBP/p300 Bromodomains Regulate Amyloid-like Protein Aggregation upon Aberrant Lysine Acetylation. Issue 1 (19th January 2017)

• Record Type: Journal Article
• Authors: Olzscha, Heidi; Fedorov, Oleg; Kessler, Benedikt M.; Knapp, Stefan; La Thangue, Nicholas B.
• Is Part Of: Cell chemical biology. Volume 24:Issue 1(2017)
• Page Start: 9
• Page End: 23
• Publication Date: 2017-01-19
• Subjects: acetylation -- aggregation -- amyloid -- bromodomain -- histone deacetylase -- p300 -- CBP -- huntingtin -- proteostasis -- inhibitor; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2016.11.009
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical Abstract: Highlights: Aberrant acetylation causes amyloid-like aggregation and disturbs proteostasis p300/CBP bromodomain proteins are involved in the protein aggregation p300/CBP bromodomain inhibitors reverse the cytotoxicity and restore proteostasis Bromodomain inhibitors also decrease pathological huntingtin protein aggregation Abstract : Olzscha et al. demonstrate that aberrantly acetylated proteins form amyloid-like aggregates in human cells. Inhibition of the p300/CBP bromodomains with small-molecule inhibitors reverses the aggregation-induced cytotoxicity. Aggregates caused by a pathologically elongated huntingtin behave in a similar way.