PCAF公司
溴尿嘧啶
乙酰转移酶
背景(考古学)
P300-CBP转录因子
免疫系统
生物
细胞生物学
癌症研究
表观遗传学
化学
分子生物学
乙酰化
免疫学
生物化学
基因
组蛋白乙酰转移酶
古生物学
作者
Zuni I. Bassi,Martin C Fillmore,Afjal H. Miah,Trevor Chapman,Claire Maller,Emma J. Roberts,Lauren Davis,Darcy E. Lewis,N. W. Galwey,Kirsty E. Waddington,Valentino Parravicini,Abigail L. Macmillan-Jones,Céline Gongora,P. G. Humphreys,Ian Churcher,Rab K. Prinjha,David F. Tough
标识
DOI:10.1021/acschembio.8b00705
摘要
P300/CBP-associated factor (PCAF) and general control nonderepressible 5 (GCN5) are closely related epigenetic proteins, each containing an acetyltransferase domain and a bromodomain. Consistent with reported roles for these proteins in immune function, we find that PCAF-deficient macrophages exhibit a markedly reduced ability to produce cytokines upon stimulation with lipopolysaccharide (LPS). Investigating the potential to target this pathway pharmacologically, we show that chemical inhibition of the PCAF/GCN5 bromodomains is insufficient to recapitulate the diminished inflammatory response of PCAF-deficient immune cells. However, by generating the first PCAF/GCN5 proteolysis targeting chimera (PROTAC), we identify small molecules able to degrade PCAF/GCN5 and to potently modulate the expression of multiple inflammatory mediators in LPS-stimulated macrophages and dendritic cells. Our data illustrate the power of the PROTAC approach in the context of multidomain proteins, revealing a novel anti-inflammatory therapeutic opportunity for targeting PCAF/GCN5.
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