Negative regulation of the interferon response by an interferon-induced long non-coding RNA

Abstract

Long non-coding RNAs (lncRNAs) play critical roles in diverse cellular processes; however, their involvement in many critical aspects of the immune response including the interferon (IFN) response remains poorly understood. To address this gap, we compared the global gene expression pattern of primary human hepatocytes before and at three time points after treatment with IFN-α. Among ∼200 IFN-induced lncRNAs, one transcript showed ∼100-fold induction. This RNA, which we named lncRNA-CMPK2, was a spliced, polyadenylated nuclear transcript that was induced by IFN in diverse cell types from human and mouse. Similar to protein-coding IFN-stimulated genes (ISGs), its induction was dependent on JAK-STAT signaling. Intriguingly, knockdown of lncRNA-CMPK2 resulted in a marked reduction in HCV replication in IFN-stimulated hepatocytes, suggesting that it could affect the antiviral role of IFN. We could show that lncRNA-CMPK2 knockdown resulted in upregulation of several protein-coding antiviral ISGs. The observed upregulation was caused by an increase in both basal and IFN-stimulated transcription, consistent with loss of transcriptional inhibition in knockdown cells. These results indicate that the IFN response involves a lncRNA-mediated negative regulatory mechanism. lncRNA-CMPK2 was strongly upregulated in a subset of HCV-infected human livers, suggesting a role in modulation of the IFN response in vivo.

Long noncoding RNA #32 contributes to antiviral responses by controlling interferon-stimulated gene expression

“…Other antiviral-related lncRNAs such as NRAV and lncRNA-CMPK2 are also negative regulators of antiviral gene expression, including ISGs (20,21). Moreover, previous studies reported that BISPR positively regulates the expression of BST2, which is a protein-coding ISG (22,23).…”

“…A number of lncRNAs are induced by viral infection or IFN-β (18,19). lncRNA-CMPK2, which is stimulated by IFN-α through the JAK-STAT pathway, suppresses the expression of ISGs such as IFIT3, ISG15, and IFITM1 (20). Influenza A virus-induced lncRNA (NRAV) inhibits the host response to viral infection by suppressing ISG expression (21).…”

Evading innate immunity in nonviral mRNA delivery: don’t shoot the messenger

“…A commonly used JAK inhibitor is the small molecule ruxolitinib [111]. Ruxolitinib potently inhibits the phosphorylation of JAK1 and can therefore interrupt IFN-JAK-STAT signaling in mRNAstimulated cells.…”

The STAT3-regulated long non-coding RNA Lethe promote the HCV replication

“…Among all types of ncRNAs, long non-coding RNAs (lncRNAs), a regulatory ncRNAs, play critical roles in almost every aspect of cellular processes [8]. Quan Zhang et al found NEAT1 to be one of several lncRNAs whose expression is changed by HIV-1 infection, and the knockdown of NEAT1 enhanced HIV-1 production through increased nucleus-to-cytoplasm export of Rev-dependent instability element (INS)-containing HIV-1 mRNAs [9].…”

“…Most recently, Hiroto Kambara et al reported that IFN-induced lncRNA-CAPK2 has an inhibitory effort on transcription of IFNstimulated antiviral genes, which suggest that CMPK2 acts as a negative regulator of IFN response [8]. Despite these discoveries, the role of lncRNAs in key aspects of the immune response, including the nearly ubiquitous and functionally crucial interferon (IFN) response remains to further investigation.…”