| First Author | Zheng Y | Year | 2023 |
| Journal | J Immunol | Volume | 210 |
| Issue | 9 | Pages | 1222-1235 |
| PubMed ID | 36961449 | Mgi Jnum | J:336763 |
| Mgi Id | MGI:7471355 | Doi | 10.4049/jimmunol.2200639 |
| Citation | Zheng Y, et al. (2023) CARD19, a Novel Regulator of the TAK1/NF-kappaB Pathway in Self-Reactive B Cells. J Immunol 210(9):1222-1235 |
| abstractText | The caspase recruitment domain family member (CARD)11-Bcl10-Malt1 signalosome controls TGF-beta-activated kinase 1 (TAK1) activation and regulates BCR-induced NF-kappaB activation. In this study, we discovered that CARD19 interacted with TAK1 and inhibited TAB2-mediated TAK1 ubiquitination and activation. Although CARD19 deficiency in mice did not affect B cell development, it enhanced clonal deletion, receptor editing, and anergy of self-reactive B cells, and it reduced autoantibody production. Mechanistically, CARD19 deficiency increased BCR/TAK1-mediated NF-kappaB activation, leading to increased expression of transcription factors Egr2/3, as well as the E3 ubiquitin ligases c-Cbl/Cbl-b, which are known inducers of B cell tolerance in self-reactive B cells. RNA sequencing analysis revealed that although CARD19 deficiency did not affect the overall Ag-induced gene expression in naive B cells, it suppressed BCR signaling and increased hyporesponsiveness of self-reactive B cells. As a result, CARD19 deficiency prevented Bm12-induced experimental systemic lupus erythematosus. In summary, CARD19 negatively regulates BCR/TAK1-induced NF-kappaB activation and its deficiency increases Egr2/3 and c-Cbl/Cbl-b expression in self-reactive B cells, thereby enhancing B cell tolerance. |
