An interferon-independent lncRNA promotes viral replication by modulating cellular metabolism

Abstract

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.

Genetic Models Reveal cis and trans Immune-Regulatory Activities for lincRNA-Cox2

“…These trans -acting lincRNAs, such as FOXF1 adjacent non-coding developmental regulatory RNA (FENDRR), long-intergenic non-coding-erythroid prosurvival (linc-EPS), and Nettoie Salmonella pasTheiler’s (NeST), can function to regulate chromatin states (Atianand et al, 2016; Gomez et al, 2013; Grote et al, 2013; Sauvageau et al, 2013), influence nuclear structure and organization (Rinn and Guttman, 2014), or interact with and regulate the behavior of proteins and/or other RNA molecules (Covarrubias et al, 2017; Kawasaki et al, 2018; Lee et al, 2016; Wang et al, 2017). …”

Viruses hijack a long non-coding RNA

“…Viral co-option of a cellular long non-protein-coding RNA has now been found to be a key step in this process. 3 report that VSV triggers transcription of a long non-protein-coding RNA called lncRNA-ACOD1 in the host-cell nucleus. LncRNA-ACOD1 moves to the cytoplasm, where it binds to and promotes the activity of the metabolic enzyme glutamic-oxaloacetic transaminase 2 (GOT2).…”

“…Analysis of the roles of cellular and viral lncRNAs in infection has previously focused mainly on modulation of innate immune responses 2 . Now, writing in Science, Wang et al 3 reveal a different mechanism by which the virus appropriates host-derived lncRNA: activation of a host-cell metabolic pathway required for viral replication.…”

GOTcha: lncRNA-ACOD1 targets metabolism during viral infection

“…While some studies have discovered regulation of metabolism by lncRNAs and other noncoding RNAs [3,8,9], few have linked metabolic reprogramming during infection with lncRNAs. In a new study in Science, Wang et al [10] investigated the role of lncRNAs during viral infection and found that a specific lncRNA binds and enhances activity of the metabolic enzyme GOT2, which alters host metabolism to benefit viral replication ( Figure 1). …”