| First Author | Shirai T | Year | 2023 |
| Journal | Sci Immunol | Volume | 8 |
| Issue | 81 | Pages | eadc9324 |
| PubMed ID | 37000855 | Mgi Jnum | J:337427 |
| Mgi Id | MGI:7494377 | Doi | 10.1126/sciimmunol.adc9324 |
| Citation | Shirai T, et al. (2023) Celastrol suppresses humoral immune responses and autoimmunity by targeting the COMMD3/8 complex. Sci Immunol 8(81):eadc9324 |
| abstractText | 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. |
