| First Author | Wei Z | Year | 2019 |
| Journal | Sci Immunol | Volume | 4 |
| Issue | 41 | PubMed ID | 31784498 |
| Mgi Jnum | J:292926 | Mgi Id | MGI:6451335 |
| Doi | 10.1126/sciimmunol.aaw5618 | Citation | Wei Z, et al. (2019) Pathogenic CARD11 mutations affect B cell development and differentiation through a noncanonical pathway. Sci Immunol 4(41) |
| abstractText | Pathogenic CARD11 mutations cause aberrant nuclear factor kappaB (NF-kappaB) activation, which is presumably responsible for multiple immunological disorders. However, whether there is an NF-kappaB-independent regulatory mechanism contributing to CARD11 mutations related to pathogenesis remains undefined. Using three distinct genetic mouse models, the Card11 knockout (KO) mouse model mimicking primary immunodeficiency, the CARD11 E134G point mutation mouse model representing BENTA (B cell expansion with NF-kappaB and T cell anergy) disease, and the mouse model bearing oncogenic K215M mutation, we show that CARD11 has a noncanonical function as a negative regulator of the AKT-FOXO1 signal axis, independent of NF-kappaB activation. Although BENTA disease-related E134G mutant elevates NF-kappaB activation, we find that E134G mutant mice phenotypically copy Card11 KO mice, in which NF-kappaB activation is disrupted. Mechanistically, the E134G mutant causes exacerbated AKT activation and reduced FOXO1 protein in B cells similar to that in Card11 KO cells. Moreover, the oncogenic CARD11 mutant K215M reinforces the importance of the noncanonical function of CARD11. In contrast to the E134G mutant, K215M shows a stronger inhibitory effect on AKT activation and more stabilized FOXO1. Likewise, E134G and K215M mutants have converse impacts on B cell development and differentiation. Our results demonstrate that, besides NF-kappaB, CARD11 also governs the AKT/FOXO1 signaling pathway in B cells. The critical role of CARD11 is further revealed by the effects of pathogenic CARD11 mutants on this noncanonical regulatory function on the AKT-FOXO1 signaling axis. |
