JAB1 Is Essential for B Cell Development and Germinal Center Formation and Inversely Regulates Fas Ligand and Bcl6 Expression
JAB1 Is Essential for B Cell Development and Germinal Center Formation and Inversely Regulates Fas Ligand and Bcl6 Expression
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DOI：
10.4049/jimmunol.1101455
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发表时间：
2012-03-15
影响因子：
4.4
通讯作者：
Gessner, Andre
中科院分区：
文献类型：
--
作者：
Sitte, Selina;Glaesner, Joachim;Gessner, Andre
Jun激活结构域结合蛋白1（JAB 1）通过基于cullin的泛素连接酶的去脱氧化来调节泛素依赖性蛋白质降解，因此在调节增殖和凋亡中起核心作用。由于这些过程是决定性的B细胞的发展，我们研究了JAB 1功能在B细胞建立一个小鼠品系与B细胞特异性JAB 1缺失。我们表明，JAB 1是必不可少的早期B细胞的发展，因为消融JAB 1表达块B细胞之间的前B和前B细胞阶段的发展。此外，JAB 1缺失导致促凋亡触发蛋白Fas配体在pro-B细胞中的异常表达。伴随的抗凋亡蛋白Bcl 2的B细胞特异性过表达部分逆转了B细胞发育的阻滞;拯救的JAB 1缺陷型B细胞到达外周，并在伯氏疏螺旋体感染后产生保护性类别转换抗体。有趣的是，B细胞拯救的小鼠没有表现出生发中心，但有显著的滤泡外浆细胞积聚。此外，JAB 1是Bcl 6表达所必需的，Bcl 6是生发中心形成所需的转录抑制因子。这些发现确定JAB 1是早期B细胞发育过程中检查点控制以及成熟Ag致敏B细胞命运决定的重要因素。免疫学杂志，2012，188：2677-2686。
Jun activation domain-binding protein 1 (JAB1) regulates ubiquitin-dependent protein degradation by deneddylation of cullin-based ubiquitin ligases and, therefore, plays a central role in regulating proliferation and apoptosis. Because these processes are decisive for B cell development, we investigated JAB1 functions in B cells by establishing a mouse strain with a B cell-specific JAB1 deletion. We show that JAB1 is essential for early B cell development, because the ablation of JAB1 expression blocks B cell development between the pro-B and pre-B cell stages. Furthermore, JAB1 deletion leads to aberrant expression of the apoptosis-triggering protein Fas ligand in pro-B cells. Concomitant B cell-specific overexpression of the antiapoptotic protein Bcl2 partially reverses the block in B cell development; rescued JAB1-deficient B cells reach the periphery and produce protective class-switched Abs after Borrelia burgdorferi infection. Interestingly, B cell-rescued mice exhibit no germinal centers but a striking extrafollicular plasma cell accumulation. In addition, JAB1 is essential for Bcl6 expression, a transcriptional repressor required for germinal center formation. These findings identify JAB1 as an important factor in checkpoint control during early B cell development, as well as in fate decisions in mature Ag-primed B cells. The Journal of Immunology, 2012, 188: 2677-2686.