Hepatitis C virus evades IFN signaling by suppressing long non-coding RNA Linc-Pint involving c/EBP-β
Hepatitis C virus (HCV) regulates many cellular genes in modulating host immune system for benefit of viral replication and long-term persistence in a host for chronic infection. Long non-coding RNAs (lncRNAs) play an important role in the regulation of many important cellular processes, including immune responses. We recently reported that HCV infection downregulates lncRNA Linc-Pint expression, although the mechanism of repression and functional consequence are not well understood. In this study, we demonstrated that HCV infection of hepatocytes transcriptionally reduces Linc-Pint expression through CCAAT/enhancer binding protein-β (C/EBP-β). Subsequently, we observed that overexpression of Linc-Pint significantly upregulates IFN-α and IFN-β expression in HCV replicating hepatocytes. Using unbiased proteomics, we identified Linc-Pint associates with DDX24, which enables RIP1 to interact with IRF7 of IFN signaling pathway. We further observed that IFN-α-14 promoter activity was enhanced in the presence of Linc-Pint. Together, these results demonstrated that Linc-Pint acts as a positive regulator of host innate immune responses, specially IFN signaling. HCV mediated downregulation of Linc-Pint expression appeared as one of the mechanisms by which HCV may evade innate immunity for long-term persistence and chronicity. IMPORTANCE The mechanism by which lncRNA regulates host immune response during HCV infection is poorly understood. We observed that Linc-Pint was transcriptionally downregulated by HCV. Using ChIP assay, we showed inhibition of transcription factor C/EBP-β binding to the Linc-pint promoter in the presence of HCV infection. We further identified that Linc-Pint associates with DDX24 for immune modulatory function. Overexpression of Linc-Pint reduces DDX24 expression which in turn results in disruption of DDX24-RIP1 complex formation and activation of IRF7. An induction of IFN-α14 promoter activity in the presence of Linc-Pint further confirms our observation. Together, our results suggest that Linc-Pint acts as a positive regulator of host innate immune response. Downregulation of Linc-Pint expression by HCV helps in escaping innate immune system for development of chronicity.