Iso-seco-tanapartholide activates Nrf2 signaling pathway through Keap1 modification and oligomerization to exert anti-inflammatory effects.
Iso-seco-tanapartholide activates Nrf2 signaling pathway through Keap1 modification and oligomerization to exert anti-inflammatory effects.
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DOI：
10.1016/j.freeradbiomed.2021.12.259
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发表时间：
2021-12
影响因子：
7.4
通讯作者：
Dongrong Zhu;Yuan-zheng Xia;Shun-Jie Li;Min-yi Kong;Chen Chen-Chen;Guimin Xue;L. Kong;Jianguang Luo-
中科院分区：
文献类型：
--
作者：
Dongrong Zhu;Yuan-zheng Xia;Shun-Jie Li;Min-yi Kong;Chen Chen-Chen;Guimin Xue;L. Kong;Jianguang Luo-
Keap 1的共价修饰导致Nrf 2的泛素化和积累减少，随后启动细胞抗氧化和抗炎基因的转录。异断烷二萜（Iso-seco-tanaparthalene，IST）是从中药青蒿中分离得到的一种倍半萜，具有抑制NF-κB的活性。但其深层抗炎作用和直接靶点的研究尚未见报道。在这里，我们表明IST激活Nrf 2并增加其靶基因表达。特别是，LPS引起的体外和体内炎症可通过IST诱导的Nrf 2激活而减轻，但可通过Nrf 2抑制而加重。在机械上，IST通过烷基化Keap 1蛋白的半胱氨酸残基151、273、288等，随后通过分子间巯基二硫键交换取代修饰剂IST，形成Keap 1的二硫键二聚体。Keap 1的构象变化使Nrf 2从隔离中释放出来，并使其易位到细胞核中激活转录程序。进一步的研究表明，Keap 1二聚体的形成有助于IST的抗炎作用。总之，我们的研究结果揭示了Nrf 2激活的新机制，并提供了一种潜在的先导化合物，通过靶向Keap 1治疗炎症性疾病。
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 medicineArtemisiaargyi, 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 inflammationin vitroandin vivowas 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.