CARD 19, a novel regulator of the TAK1/NF-κB pathway in self-reactive B cells

The CARD11-Bcl10-Malt1 signalosome controls TAK1 activation and regulates B-cell receptor (BCR)-induced NF-κB activation. Here we discovered that caspase recruitment domain family member 19 (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 reduced autoantibody production. Mechanistically, CARD19 deficiency increased BCR/TAK1-mediated NF-κB activation, leading to increased expression of transcription factors, Egr2/3, and 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 while CARD19 deficiency did not affect the overall antigen-induced gene expression in naïve 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.