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

Cellular & Molecular Immunology volume 16, pages 757–769 (2019)Cite this article

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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.

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Acknowledgements

We would like to thank Dr. Kevan M Shokat (UCSF) for generously providing pp242 and Dr. William Sessa (Yale University) for providing the Akt1-Akt2− bone marrow samples. We would like to thank Dr. Biao He (Fudan University) for assisting with the PR8 virus challenge. We also want to thank Dr. David Schatz (Yale University), Dr. Yuan Zhuang (Duke University) for kindly reading the manuscript and providing helpful comments. This study was partially supported by grant PR093728 (DoD to B.S.), the National Natural Science Foundation of China (grant numbers 31470845 and 81430033 to B.S., 31422020 to F.L. and 31600704 to H.H.Z.), grant 13JC1404700 from the Program of Science and Technology Commission of Shanghai Municipality (B.S.), the Ministry of Science and Technology of China (Program 2014CB943600, F.L.), and Chinese Mega Project on Infectious Diseases (No. 2018ZX10302301). F.L. is supported by the “Shu Guang” project of Shanghai Municipal Education Commission and Shanghai Education Development Foundation. A.S.L. is a recipient of Brown-Cox Fellowship from Yale University and is a Leukemia & Lymphoma Society fellow.

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  1. Adam S. Lazorchak

    Present address: EMD Serono Research & Development Institute, Inc., 45 Middlesex Tpke, Billerica, MA, 01821–3936, USA

  2. These authors contributed equally: Man Li, Adam S. Lazorchak

Authors and Affiliations

  1. 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

    Man Li, Xinxing Ouyang, Huihui Zhang, Hongzhi Liu, Lichong Yan, Jingsi Jin, Yuheng Han, Guojun Qu, Xiaobo Liu, Wenqian Zhang, Zhengfeng Yang, Chuan Ruan, Qijun Wang, Chuanxin Huang, Fubin Li & Bing Su

  2. Department of Immunobiology and the Vascular Biology and Therapeutics Program, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut, 06520, USA

    Adam S. Lazorchak, Omotooke A. Arojo, Xiaocao Xu, Dou Liu & Bing Su

  3. Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Huihui Zhang, Xiaobo Liu, Wenqian Zhang & Fubin Li

  4. Shanghai Public Health Clinical Center and School of Basic Medical Sciences, Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai, China

    Yuhong Fu, Lu Lu & Shibo Jiang

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Contributions

F.L., A.S.L. and B.S. conceived and designed the experiments and wrote the paper. M.L. and A.S.L. performed the experiments, analyzed the data and wrote the paper. X.O. generated the Sin1fl/fl mice. O.A., X.X., D.L., Q.W., L.Y., J.J. and Y.H. performed the experiments. A.S.L., O.A., X.X. and D.L. performed the fetal liver transplantation, in vitro pro-B cell culture and immunoblotting. B cell development analyses were performed by M.L. X.B.L, W.Q.Z and H.H.Z. Flow cytometry, model antigen immunization, the PR8 virus infection assay and B cell metabolic measurements were performed by M.L., X.O., G.Q., Y.F., L.L., S.J., and Q.W. C.H., C.R., and Z.Y. discussed the data.

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Correspondence to Fubin Li or Bing Su.

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Li, M., Lazorchak, A.S., Ouyang, X. et al. Sin1/mTORC2 regulate B cell growth and metabolism by activating mTORC1 and Myc. Cell Mol Immunol 16, 757–769 (2019). https://doi.org/10.1038/s41423-018-0185-x

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