Pathogenic CARD11 mutations affect B cell development and differentiation through a noncanonical pathway
Pathogenic CARD11 mutations affect B cell development and differentiation through a noncanonical pathway
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致病性 CARD11 突变通过非经典途径影响 B 细胞发育和分化
DOI：
10.1126/sciimmunol.aaw5618
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发表时间：
2019-11-01
影响因子：
24.8
通讯作者：
Lu, Wei
中科院分区：
文献类型：
--
作者：
Wei, Zheng;Zhang, Yan;Lu, Wei
致病性CARD11突变导致异常的核因子κB（NF - κB）激活，这可能是多种免疫疾病的原因。然而，是否存在一种不依赖NF - κB的调节机制对与发病机制相关的CARD11突变起作用仍未明确。利用三种不同的基因小鼠模型，即模拟原发性免疫缺陷的Card11基因敲除（KO）小鼠模型、代表BENTA（伴有NF - κB的B细胞扩增和T细胞无能）疾病的CARD11 E134G点突变小鼠模型以及携带致癌K215M突变的小鼠模型，我们表明CARD11具有作为AKT - FOXO1信号轴负调节因子的非经典功能，且不依赖于NF - κB激活。尽管与BENTA疾病相关的E134G突变体提高了NF - κB的激活，但我们发现E134G突变小鼠在表型上与Card11 KO小鼠相似，而在Card11 KO小鼠中NF - κB激活被破坏。从机制上讲，E134G突变体导致B细胞中AKT激活加剧和FOXO1蛋白减少，这与Card11 KO细胞中的情况相似。此外，致癌的CARD11突变体K215M进一步强调了CARD11非经典功能的重要性。与E134G突变体相反，K215M对AKT激活表现出更强的抑制作用，且使FOXO1更加稳定。同样，E134G和K215M突变体对B细胞的发育和分化具有相反的影响。我们的研究结果表明，除了NF - κB，CARD11还调控B细胞中的AKT/FOXO1信号通路。致病性CARD11突变体对AKT - FOXO1信号轴的这种非经典调节功能的影响进一步揭示了CARD11的关键作用。
Pathogenic CARD11 mutations cause aberrant nuclear factor kappa B (NF-kappa B) activation, which is presumably responsible for multiple immunological disorders. However, whether there is an NF-O-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-O 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-O activation. Although BENTA disease-related E134G mutant elevates NF-kappa B activation, we find that E134G mutant mice phenotypically copy Card11 KO mice, in which NF-O 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-O, 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.