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

• Published in: Cell metabolism 2021-05, Vol.33 (5), p.971-987.e6
• Main Authors: Shen, Long, Hu, Penghui, Zhang, Yanan, Ji, Zemin, Shan, Xiao, Ni, Lina, Ning, Na, Wang, Jing, Tian, He, Shui, Guanghou, Yuan, Yukang, Li, Guoli, Zheng, Hui, Yang, Xiang-Ping, Huang, Dandan, Feng, Xiangling, Li, Mulin Jun, Liu, Zhe, Wang, Ting, Yu, Qiujing
• Format: Article
• Language: English
• Subjects: Animals; antiviral; ATP6V0d2; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line; H3K27me3; Histones - metabolism; Humans; Immunity, Innate; Interferon-beta - genetics; Interferon-beta - metabolism; Lysosomes - metabolism; Macrophages - cytology; Macrophages - metabolism; Macrophages - virology; Mice; Mice, Inbred C57BL; Mice, Knockout; PHGDH; Phosphoglycerate Dehydrogenase - antagonists & inhibitors; Phosphoglycerate Dehydrogenase - genetics; Phosphoglycerate Dehydrogenase - metabolism; RNA Interference; RNA, Small Interfering - metabolism; S-Adenosylmethionine - pharmacology; SAM; Serine - metabolism; Signal Transduction - drug effects; Transcription Factors - genetics; Transcription Factors - metabolism; Vacuolar Proton-Translocating ATPases - genetics; Vacuolar Proton-Translocating ATPases - metabolism; Vesicular stomatitis Indiana virus - physiology; YAP
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2021.03.006

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. [Display omitted] •Enzymes of SGOC metabolism are downregulated upon virus infection•PHGDH inhibition and SG starvation enhance antiviral innate immunity in vitro and in vivo•SG deficiency increases the expression of ATP6V0d2 by inhibiting SAM-dependent H3K27me3•ATP6V0d2 promotes YAP lysosomal degradation to enhance IFN-β production Host cells co-regulate their metabolism with innate immune activation to counter virus infection. Shen et al. reveal a critical role for serine metabolism in blocking antiviral innate immunity and show that serine metabolism deficiency reduces SAM-mediated H3K27me3 and promotes ATP6V0d2 expression to enhance YAP lysosomal degradation and virus-induced IFN-β production.