Celastrol, a bioactive molecule extracted from the Tripterygium wilfordii plant, has been shown to exhibit anti-inflammatory properties. However, its mechanism of action has not been fully elucidated. Here, we show that celastrol suppresses humoral immune responses and autoimmunity by disabling a protein complex consisting of copper metabolism MURR1 domain–containing (COMMD) 3 and COMMD8 (COMMD3/8 complex), a signaling adaptor for chemoattractant receptors. Having demonstrated the involvement of the COMMD3/8 complex in a mouse model of rheumatoid arthritis, we identified celastrol as a compound that covalently bound to and dissociated the COMMD3/8 complex. Celastrol inhibited B cell migration, reduced antibody responses, and blocked arthritis progression, recapitulating deficiency of the COMMD3/8 complex. These effects of celastrol were abolished in mice expressing a celastrol-resistant mutant of the COMMD3/8 complex. These findings establish that celastrol exerts immunosuppressive activity by targeting the COMMD3/8 complex. Our study suggests that the COMMD3/8 complex is a potentially druggable target in autoimmune diseases and points to celastrol as a lead pharmacologic candidate in this capacity.

中文翻译：

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Celastrol 通过靶向 COMMD3/8 复合物抑制体液免疫反应和自身免疫

Celastrol，一种从中提取的生物活性分子雷公藤植物，已被证明具有抗炎特性。然而，其作用机制尚未完全阐明。在这里，我们表明雷公藤红素通过禁用由含铜代谢 MURR1 结构域 (COMMD) 3 和 COMMD8（COMMD3/8 复合物）组成的蛋白质复合物来抑制体液免疫反应和自身免疫，后者是趋化受体的信号转导接头。在证明 COMMD3/8 复合物参与类风湿性关节炎小鼠模型后，我们将雷公藤酚鉴定为一种共价结合并解离 COMMD3/8 复合物的化合物。Celastrol 抑制 B 细胞迁移，降低抗体反应，并阻断关节炎进展，重现 COMMD3/8 复合物的缺陷。在表达 COMMD3/8 复合物的抗雷公藤素突变体的小鼠中，雷公藤醇的这些作用被消除了。这些发现表明，雷公藤红素通过靶向 COMMD3/8 复合体发挥免疫抑制活性。我们的研究表明，COMMD3/8 复合物是自身免疫性疾病的潜在药物靶标，并指出雷公藤红素是这方面的主要药理学候选药物。