Microbiological Institute-Clinical Microbiology, Immunology and Hygiene, University Hospital Erlangen, 91054 Erlangen, Germany.
J Immunol. 2012 Mar 15;188(6):2677-86. doi: 10.4049/jimmunol.1101455. Epub 2012 Feb 10.
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.
Jun 激活域结合蛋白 1（JAB1）通过去泛素化基于 cullin 的泛素连接酶来调节泛素依赖性蛋白降解，因此在调节增殖和凋亡中发挥核心作用。由于这些过程对 B 细胞发育至关重要，我们通过建立一种 B 细胞特异性 JAB1 缺失的小鼠品系来研究 JAB1 在 B 细胞中的功能。我们表明 JAB1 对于早期 B 细胞发育是必不可少的，因为 JAB1 表达的缺失阻断了 pro-B 和 pre-B 细胞阶段之间的 B 细胞发育。此外，JAB1 缺失导致凋亡触发蛋白 Fas 配体在 pro-B 细胞中的异常表达。同时在 B 细胞特异性过表达抗凋亡蛋白 Bcl2 部分逆转了 B 细胞发育的阻断；拯救的 JAB1 缺陷 B 细胞到达外周，并在 Borrelia burgdorferi 感染后产生保护性类别转换 Ab。有趣的是，B 细胞拯救的小鼠没有生发中心，但滤泡外浆细胞明显积聚。此外，JAB1 对于 Bcl6 表达是必需的，Bcl6 是生发中心形成所必需的转录抑制剂。这些发现确定了 JAB1 作为早期 B 细胞发育过程中检查点控制以及成熟 Ag 激活的 B 细胞中命运决定的重要因素。
