Sin1/mTORC2 通过激活 mTORC1 和 Myc 来调节 B 细胞的生长和代谢。
Sin1/mTORC2 regulate B cell growth and metabolism by activating mTORC1 and Myc.
机构信息
Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Department of Immunobiology and the Vascular Biology and Therapeutics Program, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut, 06520, USA.
出版信息
Cell Mol Immunol. 2019 Sep;16(9):757-769. doi: 10.1038/s41423-018-0185-x. Epub 2019 Jan 31.
Abstract
Proper control of B cell growth and metabolism is crucial for B-cell-mediated immunity, but the underlying molecular mechanisms remain incompletely understood. In this study, Sin1, a key component of mTOR complex 2 (mTORC2), specifically regulates B cell growth and metabolism. Genetic ablation of Sin1 in B cells reduces the cell size at either the transitional stage or upon antigen stimulation and severely impairs metabolism. Sin1 deficiency also severely impairs B-cell proliferation, antibody responses, and anti-viral immunity. At the molecular level, Sin1 controls the expression and stability of the c-Myc protein and maintains the activity of mTORC1 through the Akt-dependent inactivation of GSK3 and TSC1/2, respectively. Therefore, our study reveals a novel and specific role for Sin1 in coordinating the activation of mTORC2 and mTORC1 to control B cell growth and metabolism.
摘要
正确控制 B 细胞的生长和代谢对于 B 细胞介导的免疫至关重要，但潜在的分子机制仍不完全清楚。在这项研究中，mTORC2 的关键组成部分 Sin1 特异性调节 B 细胞的生长和代谢。B 细胞中 Sin1 的基因缺失会降低过渡阶段或抗原刺激时的细胞大小，并严重损害代谢。Sin1 缺乏也严重损害 B 细胞的增殖、抗体反应和抗病毒免疫。在分子水平上，Sin1 通过 Akt 依赖性失活 GSK3 和 TSC1/2 分别控制 c-Myc 蛋白的表达和稳定性，并维持 mTORC1 的活性。因此，我们的研究揭示了 Sin1 在协调 mTORC2 和 mTORC1 的激活以控制 B 细胞生长和代谢方面的新的和特异性作用。
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