Celastrol suppresses humoral immune responses and autoimmunity by targeting the COMMD3/8 complex

Celastrol, a bioactive molecule extracted from the Tripterygium wilfordii plant, has been shown to exhibit antiinflammatory 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.

Automated summary

Celastrol can suppress humoral immune responses and autoimmunity by disabling the COMMD3/8 complex, a protein complex involved in chemotaxis and inflammation. Celastrol's immunosuppressive activity suggests that the COMMD3/8 complex could be a potential target for treating autoimmune diseases.