National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
Science. 2017 Nov 24;358(6366):1051-1055. doi: 10.1126/science.aao0409. Epub 2017 Oct 26.
Viruses regulate host metabolic networks to improve their survival. The molecules that are responsive to viral infection and regulate such metabolic changes are hardly known, but are essential for understanding viral infection. Here we identify a long noncoding RNA (lncRNA) that is induced by multiple viruses, but not by type I interferon (IFN-I), and facilitates viral replication in mouse and human cells. In vivo deficiency of lncRNA-ACOD1 (a lncRNA identified by its nearest coding gene , aconitate decarboxylase 1) significantly attenuates viral infection through IFN-I-IRF3 (interferon regulatory factor 3)-independent pathways. Cytoplasmic lncRNA-ACOD1 directly binds the metabolic enzyme glutamic-oxaloacetic transaminase (GOT2) near the substrate niche, enhancing its catalytic activity. Recombinant GOT2 protein and its metabolites could rescue viral replication upon lncRNA-ACOD1 deficiency and increase lethality. This work reveals a feedback mechanism of virus-induced lncRNA-mediated metabolic promotion of viral infection and a potential target for developing broad-acting antiviral therapeutics.
病毒调节宿主代谢网络以提高其存活率。响应病毒感染并调节这种代谢变化的分子尚不清楚，但对于理解病毒感染至关重要。在这里，我们鉴定了一种长非编码 RNA（lncRNA），它被多种病毒诱导，但不受 I 型干扰素（IFN-I）的影响，并促进小鼠和人类细胞中的病毒复制。体内缺乏 lncRNA-ACOD1（由其最近的编码基因 aconitate decarboxylase 1 鉴定的 lncRNA）通过 IFN-I-IRF3（干扰素调节因子 3）非依赖性途径显著减弱病毒感染。细胞质 lncRNA-ACOD1 直接结合靠近底物位的代谢酶谷氨酸草酰乙酸转氨酶（GOT2），增强其催化活性。重组 GOT2 蛋白及其代谢物可在 lncRNA-ACOD1 缺乏时挽救病毒复制，并增加致死率。这项工作揭示了病毒诱导的 lncRNA 介导的代谢促进病毒感染的反馈机制，以及开发广泛作用的抗病毒治疗的潜在靶点。
