CARD19, a Novel Regulator of the TAK1/NF-κB Pathway in Self-Reactive B Cells
| Autor: | Yongwei Zheng, Mei Yu, Yuhong Chen, Liquan Xue, Wen Zhu, Guoping Fu, Stephan W. Morris, Renren Wen, Demin Wang |
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| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 210:1222-1235 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | The caspase recruitment domain family member (CARD)11-Bcl10-Malt1 signalosome controls TGF-β–activated kinase 1 (TAK1) activation and regulates BCR-induced NF-κB 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-κB 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-κB activation and its deficiency increases Egr2/3 and c-Cbl/Cbl-b expression in self-reactive B cells, thereby enhancing B cell tolerance. |
| Databáze: | OpenAIRE |
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