A Sesquiterpene Lactone from a Medicinal Herb Inhibits Proinflammatory Activity of TNF-α by Inhibiting Ubiquitin-Conjugating Enzyme UbcH5
A Sesquiterpene Lactone from a Medicinal Herb Inhibits Proinflammatory Activity of TNF-α by Inhibiting Ubiquitin-Conjugating Enzyme UbcH5
复制标题
来自药草的倍半萜内酯通过抑制泛素结合酶 UbcH5 抑制 TNF-α 的促炎活性
DOI：
10.1016/j.chembiol.2014.07.021
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发表时间：
2014-10-23
影响因子：
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通讯作者：
Zhang, Weidong
中科院分区：
文献类型：
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作者：
Liu, Li;Hua, Yaping;Zhang, Weidong
UbcH5 是关键的泛素结合酶，在 TNF-α 触发的 NF-κ B 激活过程中催化泛素化。在这里，我们鉴定了一种源自草药的倍半萜内酯化合物 IJ-5 作为 UbcH5 的优先抑制剂，并探索了其在炎症和自身免疫性疾病模型中的治疗价值。 IJ-5 通过抑制受体相互作用蛋白 1 和 NF-kappa B 必需修饰物的泛素化来抑制 TNF-α 诱导的 NF-kappa B 激活和炎症基因转录，这对于 I kappa B 激酶激活至关重要。机理研究表明，IJ-5 通过与其活性位点半胱氨酸形成共价加合物优先结合 UbcH5 并使其失活，从而阻止泛素与 UbcH5 缀合。在临床前模型中，IJ-5 预处理对 TNF-α 和 D-半乳糖胺诱导的肝炎和胶原诱导的关节炎表现出有效的抗炎活性。这些发现凸显了 UbcH5 作为抗 TNF-α 干预治疗靶点的潜力，并为新型抗炎药物的开发提供了一种有趣的先导化合物。
UbcH5 is the key ubiquitin-conjugating enzyme catalyzing ubiquitination during TNF-alpha-triggered NF-kappa B activation. Here, we identified an herb-derived sesquiterpene lactone compound IJ-5 as a preferential inhibitor of UbcH5 and explored its therapeutic value in inflammatory and autoimmune disease models. IJ-5 suppresses TNF-alpha-induced NF-kappa B activation and inflammatory gene transcription by inhibiting the ubiquitination of receptor-interacting protein 1 and NF-kappa B essential modifier, which is essential to I kappa B kinase activation. Mechanistic investigations revealed that IJ-5 preferentially binds to and inactivates UbcH5 by forming a covalent adduct with its active site cysteine and thereby preventing ubiquitin conjugation to UbcH5. In preclinical models, pretreatment of IJ-5 exhibited potent anti-inflammatory activity against TNF-alpha-and D-galactosamine-induced hepatitis and collagen-induced arthritis. These findings highlight the potential of UbcH5 as a therapeutic target for anti-TNF-alpha interventions and provide an interesting lead compound for the development of new anti-inflammation agents.