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 researchers at Peking Union Medical College 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 Acod1, 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.
lncRNA-ACOD1 promotes GOT2 enzymatic activity
and functions through GOT2 catalyzed metabolites
(A) GOT2 binding RNAs were analyzed by imprinting RNA-sequencing of GOT2 antibody-retrieved complexes. Data are shown as read density around lncRNA-ACOD1 loci (upper) and lncRNA-ACOD1 RNA (lower). Red bar indicates protein binding site immune to RNase I digestion. (B) Upper: lncRNA-ACOD1 retrieved GOT2 peptide identified by MS analysis and its position in GOT2 protein linear structure and spatial structure (PDB code: 3PDB) (highlighted in yellow). Lower: GOT2 protein sequence conservation in vertebrates. (C) Q-PCR detection of lncRNA-ACOD1 retrieved by full-length or domain truncated GOT2-FLAG using FLAG antibody in the RIP assay within HEK293T cells transfected with indicated vectors. C-SD, C-terminal part of the small domain; LD, large domain; N-arm, N-terminal arm; N-SD, N-terminal part of the small domain. N=3
Wang P, Xu J, Wang Y, Cao X. (2017) An interferon-independent lncRNA promotes viral replication by modulating cellular metabolism