Serine metabolism antagonizes antiviral innate immunity by preventing ATP6V0d2-mediated YAP lysosomal degradation

  • Cell Metab. 2021 May 4;33(5):971-987.e6. doi: 10.1016/j.cmet.2021.03.006.
Long Shen  1 ,  Penghui Hu  1 ,  Yanan Zhang  1 ,  Zemin Ji  1 ,  Xiao Shan  1 ,  Lina Ni  2 ,  Na Ning  3 ,  Jing Wang  3 ,  He Tian  4 ,  Guanghou Shui  4 ,  Yukang Yuan  5 ,  Guoli Li  1 ,  Hui Zheng  5 ,  Xiang-Ping Yang  3 ,  Dandan Huang  6 ,  Xiangling Feng  6 ,  Mulin Jun Li  6 ,  Zhe Liu  1 ,  Ting Wang  7 ,  Qiujing Yu  8
Affiliations
  • 1. Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
  • 2. Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
  • 3. Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 4. State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
  • 5. Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu 215123, China.
  • 6. The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
  • 7. Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China. Electronic address: [email protected].
  • 8. Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China. Electronic address: [email protected].
PMID: 33798471 DOI: 10.1016/j.cmet.2021.03.006
Abstract

Serine metabolism promotes tumor oncogenesis and regulates immune cell functions, but whether it also contributes to Antiviral innate immunity is unknown. Here, we demonstrate that virus-infected macrophages display decreased expression of serine synthesis pathway (SSP) Enzymes. Suppressing the SSP key enzyme phosphoglycerate dehydrogenase (PHGDH) by genetic approaches or by treatment with the pharmaceutical inhibitor CBR-5884 and by exogenous serine restriction enhanced IFN-β-mediated Antiviral innate immunity in vitro and in vivo. Mechanistic experiments showed that virus Infection or serine metabolism deficiency increased the expression of the V-ATPase subunit ATP6V0d2 by inhibiting S-adenosyl methionine-dependent H3K27me3 occupancy at the promoter. ATP6V0d2 promoted YAP lysosomal degradation to relieve YAP-mediated blockade of the TBK1-IRF3 axis and, thus, enhance IFN-β production. These findings implicate critical functions of PHGDH and the key immunometabolite serine in blunting Antiviral innate immunity and also suggest manipulation of serine metabolism as a therapeutic strategy against virus Infection.

Keywords
ATP6V0d2; H3K27me3; PHGDH; SAM; YAP; antiviral; serine metabolism.
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