Department of Immunobiology, Yale School of Medicine, New Haven, CT 06519, USA.
Mol Cell. 2010 Aug 13;39(3):433-43. doi: 10.1016/j.molcel.2010.07.031.
Mammalian target of rapamycin (mTOR) is an important mediator of phosphoinositol-3-kinase (PI3K) signaling. PI3K signaling regulates B cell development, homeostasis, and immune responses. However, the function and molecular mechanism of mTOR-mediated PI3K signaling in B cells has not been fully elucidated. Here we show that Sin1, an essential component of mTOR complex 2 (mTORC2), regulates B cell development. Sin1 deficiency results in increased IL-7 receptor (il7r) and RAG recombinase (rag1 and rag2) gene expression, leading to enhanced pro-B cell survival and augmented V(D)J recombinase activity. We further show that Akt2 specifically mediates the Sin1-mTORC2 dependent suppression of il7r and rag gene expression in B cells by regulating FoxO1 phosphorylation. Finally, we demonstrate that the mTOR inhibitor rapamycin induces rag expression and promotes V(D)J recombination in B cells. Our study reveals that the Sin1/mTORC2-Akt2 signaling axis is a key regulator of FoxO1 transcriptional activity in B cells.
哺乳动物雷帕霉素靶蛋白（mTOR）是磷酸肌醇 3-激酶（PI3K）信号的重要介质。PI3K 信号调节 B 细胞的发育、稳态和免疫反应。然而，mTOR 介导的 PI3K 信号在 B 细胞中的功能和分子机制尚未完全阐明。在这里，我们表明 Sin1，mTOR 复合物 2（mTORC2）的一个重要组成部分，调节 B 细胞的发育。Sin1 缺陷导致 IL-7 受体（il7r）和 RAG 重组酶（rag1 和 rag2）基因表达增加，导致前 B 细胞存活增强和 V(D)J 重组酶活性增强。我们进一步表明，Akt2 通过调节 FoxO1 磷酸化特异性介导 Sin1-mTORC2 依赖性抑制 B 细胞中 il7r 和 rag 基因表达。最后，我们证明 mTOR 抑制剂雷帕霉素诱导 B 细胞中 rag 表达并促进 V(D)J 重组。我们的研究表明，Sin1/mTORC2-Akt2 信号轴是 B 细胞中 FoxO1 转录活性的关键调节剂。
