Celastrol suppresses humoral immune responses and autoimmunity by targeting the COMMD3/8 complex
Celastrol suppresses humoral immune responses and autoimmunity by targeting the COMMD3/8 complex
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DOI：
10.1126/sciimmunol.adc9324
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发表时间：
2023-03
影响因子：
24.8
通讯作者：
Taiichiro Shirai;Akiko Nakai;Emiko Ando;J. Fujimoto;S. Leach;T. Arimori;D. Higo;Floris J. van Eerden;J. Tulyeu;Yu-Chen Liu;D. Okuzaki;Masanori A. Murayama;H. Miyata;K. Nunomura;Bangzhong Lin;Akiyoshi Tani;A. Kumanogoh;M. Ikawa;J. Wing;D. Standley;J. Takagi;Kazuhiro Suzuki
中科院分区：
文献类型：
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作者：
Taiichiro Shirai;Akiko Nakai;Emiko Ando;J. Fujimoto;S. Leach;T. Arimori;D. Higo;Floris J. van Eerden;J. Tulyeu;Yu-Chen Liu;D. Okuzaki;Masanori A. Murayama;H. Miyata;K. Nunomura;Bangzhong Lin;Akiyoshi Tani;A. Kumanogoh;M. Ikawa;J. Wing;D. Standley;J. Takagi;Kazuhiro Suzuki
雷公藤红素是一种从雷公藤植物中提取的生物活性分子，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抑制体液免疫反应和自身免疫，通过禁用由铜代谢MURR 1域含（COMMD）3和COMMD 8（COMMD 3/8复合物），化学引诱物受体的信号适配器组成的蛋白质复合物。在证明COMMD 3/8复合物参与类风湿性关节炎小鼠模型后，我们将雷公藤红素鉴定为共价结合并解离COMMD 3/8复合物的化合物。雷公藤红素抑制B细胞迁移，降低抗体反应，阻断关节炎进展，重现COMMD 3/8复合物的缺陷。雷公藤红素的这些作用在表达COMMD 3/8复合物的雷公藤红素抗性突变体的小鼠中被消除。这些发现证实雷公藤红素通过靶向COMMD 3/8复合物发挥免疫抑制活性。我们的研究表明COMMD 3/8复合物是自身免疫性疾病中的潜在药物靶点，并指出雷公藤红素作为这种能力的主要药理学候选物。描述抗炎药雷公藤红素通过破坏COMMD 3/8复合物抑制体液免疫反应并增强自身免疫。靶向关节炎中的B细胞迁移COMMD 3和COMMD 8是含铜代谢MURR 1结构域（COMMD）蛋白家族的成员，在诱导体液免疫应答期间形成化学引诱剂介导的B细胞迁移所必需的异二聚体。通过筛选能够破坏COMMD 3/8复合物的分子的化合物文库，Shirai等人鉴定了中草药雷公藤红素作为COMMD 3与COMMD 8结合的有效抑制剂。在类风湿性关节炎的小鼠模型中，在关节炎发作时开始的雷公藤红素治疗阻止了疾病进展。当COMMD 3的半胱氨酸170被丙氨酸取代时，雷公藤红素破坏COMMD 3/8复合物并抑制关节炎的能力丧失。这些发现揭示了雷公藤红素抗关节炎活性的分子机制，并鉴定了COMMD 3/8复合物作为B细胞依赖性自身免疫性疾病的潜在药物靶点。-IRW
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. Description The anti-inflammatory drug celastrol suppresses humoral immune responses and alleviates autoimmunity by disrupting the COMMD3/8 complex. Targeting B cell migration in arthritis COMMD3 and COMMD8, members of the copper metabolism MURR1 domain–containing (COMMD) protein family, form a heterodimer essential for chemoattractant-mediated B cell migration during induction of humoral immune responses. By screening a compound library for molecules capable of disrupting the COMMD3/8 complex, Shirai et al. identified the Chinese herbal medicine celastrol as a potent inhibitor of COMMD3 association with COMMD8. In a mouse model of rheumatoid arthritis, celastrol treatment initiated at the onset of arthritis prevented disease progression. Celastrol’s ability to disrupt the COMMD3/8 complex and inhibit arthritis was lost when cysteine 170 of COMMD3 was replaced with alanine. These findings reveal a molecular mechanism for the anti-arthritic activity of celastrol and identify the COMMD3/8 complex as a potential drug target in B cell-dependent autoimmune diseases. —IRW