脱甲基酶
染色质
染色质重塑
组蛋白
泛素
表观遗传学
串扰
细胞生物学
脱氮酶
DNA甲基化
转录因子
组蛋白甲基化
化学
乙酰化
生物
遗传学
基因
基因表达
光学
物理
作者
Zhiyao Zhao,Zexiong Su,Puping Liang,Di Liu,Shuai Yang,Yaoxing Wu,Ling Ma,Jiayi Feng,Xiya Zhang,Chenglei Wu,Junjiu Huang,Jun Cui
标识
DOI:10.1002/advs.202002680
摘要
Chromatin modifications, such as histone acetylation, ubiquitination, and methylation, play fundamental roles in maintaining chromatin architecture and regulating gene transcription. Although their crosstalk in chromatin remodeling has been gradually uncovered, the functional relationship between histone ubiquitination and methylation in regulating immunity and inflammation remains unclear. Here, it is reported that USP38 is a novel histone deubiquitinase that works together with the histone H3K4 modifier KDM5B to orchestrate inflammatory responses. USP38 specifically removes the monoubiquitin on H2B at lysine 120, which functions as a prerequisite for the subsequent recruitment of demethylase KDM5B to the promoters of proinflammatory cytokines Il6 and Il23a during LPS stimulation. KDM5B in turn inhibits the binding of NF-κB transcription factors to the Il6 and Il23a promoters by reducing H3K4 trimethylation. Furthermore, USP38 can bind to KDM5B and prevent it from proteasomal degradation, which further enhances the function of KDM5B in the regulation of inflammation-related genes. Loss of Usp38 in mice markedly enhances susceptibility to endotoxin shock and acute colitis, and these mice display a more severe inflammatory phenotype compared to wild-type mice. The studies identify USP38-KDM5B as a distinct chromatin modification complex that restrains inflammatory responses through manipulating the crosstalk of histone ubiquitination and methylation.
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