LncRNA JINR1 regulates miR-216b-5p/GRP78 and miR-1-3p/DDX5 axis to promote JEV infection and cell death.

Abstract

Japanese encephalitis virus (JEV) infection in the central nervous system (CNS) leads to neuroinflammation and neuronal cell death. Several long non-coding RNAs (lncRNAs) are differentially expressed during viral infection and regulate multiple aspects of viral pathogenesis. Previously, we have shown that JEV/West Nile virus (WNV) infection promotes JEV-induced non-coding RNA 1 (JINR1) expression in SH-SY5Y cells, and it interacts with RNA-binding motif protein 10 (RBM10) to enhance cell death and viral replication. In this study, we show that JEV or WNV infection of the SH-SY5Y cells inhibits the expression of microRNAs (miRNAs) miR-216b-5p and miR-1-3p. These miRNAs bind to the JEV/WNV genome, and their overexpression during JEV/WNV infection reduces viral replication and cell death. Depleting JINR1 or RBM10 during viral infection prevents the downregulation of miR-216b-5p and miR-1-3p. In addition, JINR1 or RBM10 knockdown during JEV/WNV infection enhances the binding of RNA Pol II and H3K4me3 at the promoters of miR-216b-5p and miR-1-3p. JINR1 or RBM10 depletion also prevents the binding of H3K27me3 at the promoters of these miRNAs, suggesting that JINR1 and RBM10 are involved in their transcription repression. Interestingly, JINR1 also acts as a competing endogenous RNA (ceRNA) that directly binds to miR-216b-5p and miR-1-3p, resulting in the upregulation of their targets glucose-regulated protein 78 (GRP78) and DEAD-Box Helicase 5 (DDX5), respectively, which are involved in regulating viral replication. Our findings suggest that JINR1 uses multiple mechanisms to promote JEV and WNV infection in neuronal cells.

Importance: Infection of the central nervous system (CNS) by Japanese encephalitis virus (JEV) or West Nile virus (WNV) leads to neuroinflammation and neuronal cell death. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) regulate viral infection by regulating the expression of host genes. However, knowledge about the interplay between lncRNAs and miRNAs during JEN/WNV infection is limited. We show that JEV/WNV infection inhibits the expression of anti-viral host miRNAs miR-216b-5p and miR-1-3p. These miRNAs inhibit the JEV and WNV replication by directly binding with their genome. JINR1 and its interacting protein, RBM10, inhibit the transcription of miR-216b-5p and miR-1-3p. Interestingly, JINR1 also binds and sequesters miR-216b-5p and miR-1-3p, resulting in upregulation of their targets GRP78 and DDX5, respectively, which promote viral infection. Our findings suggest that lncRNA JINR1 is a potential target for developing anti-virals against JEV/WNV infection.