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余秋景/王霆团队揭示丝氨酸代谢抑制抗病毒先天免疫的机制
作者:小柯机器人 发布时间:2021/4/4 23:02:44

2021年4月1日,天津医科大学余秋景团队和王霆团队合作发现丝氨酸代谢通过抑制ATP6V0d2介导的YAP溶酶体降解来削弱抗病毒先天免疫。相关论文在线发表《细胞—代谢》杂志上。

研究人员发现在病毒感染的巨噬细胞中与丝氨酸合成途径(SSP)有关的酶表达下降。通过遗传方法或使用药物抑制剂CBR-5884以及外源丝氨酸限制等方法抑制SSP限速酶磷酸甘油酸脱氢酶(PHGDH),在体内外均可增强IFN-β介导的抗病毒先天免疫力。

机理实验表明,病毒感染或丝氨酸代谢不足通过抑制启动子上S-腺苷甲硫氨酸依赖性H3K27me3的富集来增加V-ATPase亚基ATP6V0d2的表达。TP6V0d2可促进YAP溶酶体降解,减弱了YAP介导的TBK1-IRF3阻滞,从而增强了IFN-β的产生。

这些发现表明了PHGDH和免疫代谢丝氨酸在削弱抗病毒先天免疫中的关键功能,也揭示了靶向丝氨酸代谢作为对抗病毒感染的治疗潜能。

研究人员介绍,丝氨酸代谢促进肿瘤发生并调节免疫细胞的功能,但尚不清楚它是否也有助于抗病毒先天免疫。

附:英文原文

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

Author: Long Shen, Penghui Hu, Yanan Zhang, Zemin Ji, Xiao Shan, Lina Ni, Na Ning, Jing Wang, He Tian, Guanghou Shui, Yukang Yuan, Guoli Li, Hui Zheng, Xiang-Ping Yang, Dandan Huang, Xiangling Feng, Mulin Jun Li, Zhe Liu, Ting Wang, Qiujing Yu

Issue&Volume: 2021-04-01

Abstract: Serine metabolism promotes tumor oncogenesis and regulates immune cell functions,but whether it also contributes to antiviral innate immunity is unknown. Here, wedemonstrate that virus-infected macrophages display decreased expression of serinesynthesis pathway (SSP) enzymes. Suppressing the SSP key enzyme phosphoglycerate dehydrogenase(PHGDH) by genetic approaches or by treatment with the pharmaceutical inhibitor CBR-5884and by exogenous serine restriction enhanced IFN-β-mediated antiviral innate immunityin vitro and in vivo. Mechanistic experiments showed that virus infection or serine metabolism deficiencyincreased the expression of the V-ATPase subunit ATP6V0d2 by inhibiting S-adenosylmethionine-dependent H3K27me3 occupancy at the promoter. ATP6V0d2 promoted YAP lysosomaldegradation to relieve YAP-mediated blockade of the TBK1-IRF3 axis and, thus, enhanceIFN-β production. These findings implicate critical functions of PHGDH and the keyimmunometabolite serine in blunting antiviral innate immunity and also suggest manipulationof serine metabolism as a therapeutic strategy against virus infection.

DOI: 10.1016/j.cmet.2021.03.006

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00113-3

期刊信息

Cell Metabolism:《细胞—代谢》,创刊于2005年。隶属于细胞出版社,最新IF:22.415
官方网址:https://www.cell.com/cell-metabolism/home
投稿链接:https://www.editorialmanager.com/cell-metabolism/default.aspx