Tamahara Toru, Ochiai Kyoko, Muto Akihiko, Kato Yukinari, Sax Nicolas, Matsumoto Mitsuyo, Koseki Takeyoshi, Igarashi Kazuhiko
Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
Department of Preventive Dentistry, Tohoku University Graduate School of Dentistry, Sendai, Japan.
Mol Cell Biol. 2017 Nov 28;37(24). doi: 10.1128/MCB.00418-17. Print 2017 Dec 15.
The transcription factor Bach2 regulates both acquired and innate immunity at multiple steps, including antibody class switching and regulatory T cell development in activated B and T cells, respectively. However, little is known about the molecular mechanisms of Bach2 regulation in response to signaling of cytokines and antigen. We show here that mammalian target of rapamycin (mTOR) controls Bach2 along B cell differentiation with two distinct mechanisms in pre-B cells. First, mTOR complex 1 (mTORC1) inhibited accumulation of Bach2 protein in nuclei and reduced its stability. Second, mTOR complex 2 (mTORC2) inhibited FoxO1 to reduce mRNA expression. Using expression profiling and chromatin immunoprecipitation assay, the gene, encoding cyclin D3, was identified as a new direct target of Bach2. A proper cell cycle was lost at pre-B and mature B cell stages in -deficient mice. Furthermore, AZD8055, an mTOR inhibitor, increased class switch recombination in wild-type mature B cells but not in -deficient cells. These results suggest that the mTOR-Bach2 cascade regulates proper cell cycle arrest in B cells as well as immunoglobulin gene rearrangement.
转录因子Bach2在多个步骤中调节获得性免疫和先天性免疫，分别包括活化的B细胞和T细胞中的抗体类别转换以及调节性T细胞的发育。然而，关于Bach2响应细胞因子和抗原信号进行调节的分子机制，人们了解甚少。我们在此表明，雷帕霉素的哺乳动物靶标（mTOR）在pre-B细胞中通过两种不同机制在B细胞分化过程中控制Bach2。首先，mTOR复合物1（mTORC1）抑制Bach2蛋白在细胞核中的积累并降低其稳定性。其次，mTOR复合物2（mTORC2）抑制FoxO1以降低mRNA表达。通过表达谱分析和染色质免疫沉淀试验，编码细胞周期蛋白D3的基因被鉴定为Bach2的一个新的直接靶标。在Bach2缺陷小鼠的pre-B细胞和成熟B细胞阶段，正常的细胞周期丧失。此外，mTOR抑制剂AZD8055增加了野生型成熟B细胞中的类别转换重组，但在Bach2缺陷细胞中没有增加。这些结果表明，mTOR-Bach2级联反应调节B细胞中适当的细胞周期停滞以及免疫球蛋白基因重排。
