2. Academic Validation
  3. Serine metabolism antagonizes antiviral innate immunity by preventing ATP6V0d2-mediated YAP lysosomal degradation

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

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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