Celastrol suppresses humoral immune responses and autoimmunity by targeting the COMMD3/8 complex
Taiichiro Shirai, Akiko Nakai, Emiko Ando, Jun Fujimoto, Sarah Leach, Takao Arimori, Daisuke Higo, Floris J. van Eerden, Janyerkye Tulyeu, Yu‐Chen Liu, Daisuke Okuzaki, Masanori A. Murayama, Haruhiko Miyata, Kazuto Nunomura, Bangzhong Lin, Akiyoshi Tani, Atsushi Kumanogoh, Masahito Ikawa, James B. Wing, Daron M. Standley, Junichi Takagi, Kazuhiro Suzuki
Abstract
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.