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Metabolic regulation of T cell development by Sinl-mTORC2 is mediated by pyruvate kinase M2

Journal of Molecular Cell Biology 2019年第2期11卷 93-106页

作者： Xinxing Ouyang Yuheng Han Guojun Qu Man Li Ningbo Wu Hongzhi Liu omotooke arojo Hongxiang Sun Xiaobo Liu Dou Liu Lei Chen Qiang Zou Bing Su 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 CT 06520 USA

Glucose metabolism plays a key role in thymocyte development. The mammalian target of rapamycin complex 2 (mT0RC2) is a critical regulator of cell growth and metabolism, but its role in early thymocyte development and metabolism has not been fully studied. We show here that genetic ablation of Sinl, an essential component of mTORC2, in T lineage cells results in severely impaired thymocyte development at the CD4^- CD8^- double negative (DN) stages but not at the CD4^+ CD8^+ double positive (DP) or later stages. Notably, Sinl-deficient DN thymocytes show markedly reduced proliferation and ***, we discover that the M2 isoform of pyruvate kinase (PKM2) is a novel and crucial Sinl effector in promoting DN thymocyte development and metabolism. At the molecular level, we show that Sinl-mTORC2 controls PKM2 expression through an AKT-dependent PPAR-y nuclear translocation. Together, our study unravels a novel mTORC2-PPAR-γ-PKM2 pathway in immune-metabolic regulation of early thymocyte development.

关键词： mT0RC2 Sinl thymocyte development PPAR-γ PKM2 metabolism

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Sin1/mTORC2 regulate B cell growth and metabolism by activating mTORC1 and Myc

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Cellular & Molecular Immunology 2019年第9期16卷 757-769页

作者： Man Li Adam S.Lazorchak Xinxing Ouyang Huihui Zhang Hongzhi Liu omotooke A.arojo Lichong Yan Jingsi Jin Yuheng Han Guojun Qu Yuhong Fu Xiaocao Xu Xiaobo Liu Wenqian Zhang Zhengfeng Yang Chuan Ruan Qijun Wang Dou Liu Chuanxin Huang Lu Lu Shibo Jiang Fubin Li Bing Su Shanghai Institute of Immunology Department of Immunology and MicrobiologyKey Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of EducationShanghai Jiao Tong University School of MedicineShanghai 200025China Department of Immunobiology and the Vascular Biology and Therapeutics Program Yale University School of Medicine333 Cedar StreetNew HavenConnecticut 06520USA Present address:EMD Serono Research&Development Institute Inc.45 Middlesex TpkeBillericaMA 01821–3936USA Hongqiao International Institute of Medicine Shanghai Tongren Hospital and Faculty of Basic MedicineShanghai Jiao Tong University School of MedicineShanghai 200025China Shanghai Public Health Clinical Center and School of Basic Medical Sciences Key Laboratory of Medical Molecular Virology of MOE/MOHFudan UniversityShanghaiChina

Proper control of B cell growth and metabolism is crucial for B-cell-mediated immunity,but the underlying molecular mechanisms remain incompletely *** this study,Sin1,a key component of mTOR complex 2(mTORC2),specifically regulates B cell growth and *** ablation of Sin1 in B cells reduces the cell size at either the transitional stage or upon antigen stimulation and severely impairs ***1 deficiency also severely impairs B-cell proliferation,antibody responses,and anti-viral *** 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,***,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.

关键词： metabolism immunity stimulation

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