KEAP1型
化学
泛素
体内
半胱氨酸
细胞生物学
P50页
体外
二聚体
炎症
信号转导
转录因子
生物化学
基因
生物
酶
遗传学
免疫学
有机化学
作者
Di Zhu,Yuan‐Zheng Xia,Shang Li,Min Kong,Chen Chen,Gui‐Min Xue,Ling‐Yi Kong,Jian‐Guang Luo
标识
DOI:10.1016/j.freeradbiomed.2021.12.259
摘要
Covalent modification of Keap1 results in reducing ubiquitination and the accumulation of Nrf2, which subsequently initiates the transcription of cellular anti-oxidant and anti-inflammatory genes. Iso-seco-tanapartholide (IST), a sesquiterpene isolated from the traditional Chinese medicine Artemisia argyi, had been reported to possess NF-κB inhibitory activity. However, its deep anti-inflammatory effects and direct target have never been reported. Here we show that IST activated Nrf2 and increased its target gene expression. In particular, LPS-caused inflammation in vitro and in vivo was mitigated by IST-induced Nrf2 activation but aggravated by Nrf2 inhibition. Mechanically, IST targeted Keap1 proteins via alkylating its cysteine residues 151, 273, 288, and so on. Subsequently, the modifying agent IST was displaced by intermolecular sulfhydryl disulfide interchange to lead to a disulfide dimer of Keap1. The resulting conformational change of Keap1 liberated Nrf2 from sequestration and allowed it translocation to the nucleus to activate the transcriptional program. Further studies demonstrated that Keap1 dimer formation contributed to the anti-inflammatory effects of IST. Taken together, our findings reveal a new mechanism for Nrf2 activation and provide a potential lead compound to treat inflammatory diseases through targeting Keap1.
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