组蛋白H2B
神经炎症
泛素连接酶
小胶质细胞
细胞生物学
泛素
组蛋白
生物
炎症
生物化学
基因
免疫学
作者
Shu-Ze Zheng,Xiaowen Zhang,Xiaomin Song,Zhuo Yang,Yao Lu,Peng‐Fei Tu,Ke‐Wu Zeng
标识
DOI:10.1016/j.phrs.2022.106093
摘要
Monoubiquitination plays a critical role as one of the largest histone post-translational modifications (PTMs). Recent study has revealed that histone H2B monoubiquitination (H2Bub1) at a unique lysine 120 (K120) is widely involved in the development of inflammation progression. However, small-molecules directly targeting H2B to exert anti-inflammation effects via editing monoubiquitination have not been hitherto reported. In this study, we first discover a natural small-molecule epoxymicheliolide (ECL), which directly binds to H2B to inhibit microglia-mediated neuroinflammation in vitro and in vivo. Mechanism study suggests that ECL covalently modifies a previously undisclosed lysine 46 (K46) in H2B, and recruits E3 ubiquitin ligase RNF20 to promote H2Bub1 at K120. ChIP-seq and transcriptomics further reveal that ECL-mediated H2Bub1 markedly disrupts the AP-1 recruitment to proinflammatory gene promoters for microglia inactivation. Collectively, our findings suggests that K46 of H2B serves as a promising pharmacological target to develop small-molecule drugs against microglia-mediated neuroinflammation, and ECL represents a valuable lead compound for neuroinflammation via regulating histone monoubiquitination.
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