An RBM10 and NF-κB interacting host lncRNA promotes JEV replication and neuronal cell death

Abstract

ABSTRACT Infection of the central nervous system by the Japanese encephalitis virus (JEV) is characterized by extensive neuronal cell death and neuroinflammation. Several protein-coding genes and microRNAs are implicated in JEV-induced neuronal cell death. However, the global expression patterns and functional contributions of long non-coding RNAs (lncRNAs) during JEV-induced neuronal cell death have not been explored. Here, we profiled the transcriptome of the JEV-infected neuronal cell line and identified several lncRNAs whose expression is altered during JEV infection. We functionally characterized a lncRNA named JINR1 (JEV-induced non-coding RNA 1), which is evolutionarily conserved in primates. JINR1 induction during JEV infection is regulated by nuclear factor-kappa B (NF-κB). Depletion of JINR1 during infection reduces flavivirus replication, neuronal cell death, and the expression of genes involved in ER stress and neuroinflammation. Interestingly, GRP78 overexpression prevents the decrease in flavivirus replication due to JINR1 knockdown. JINR1 interacts with RBM10 and NF-κB to regulate the transcription of virus - induced genes. In addition, RBM10 and JINR1 form a feed-forward loop to reciprocally promote each other’s expression by regulating NF-κB activity. Our results suggest the role of JINR1 in promoting flavivirus replication and flavivirus-induced neuronal cell death. IMPORTANCE Central nervous system infection by flaviviruses such as Japanese encephalitis virus, Dengue virus, and West Nile virus results in neuroinflammation and neuronal damage. However, little is known about the role of long non-coding RNAs (lncRNAs) in flavivirus-induced neuroinflammation and neuronal cell death. Here, we characterized the role of a flavivirus-induced lncRNA named JINR1 during the infection of neuronal cells. Depletion of JINR1 during virus infection reduces viral replication and cell death. An increase in GRP78 expression by JINR1 is responsible for promoting virus replication. Flavivirus infection induces the expression of a cellular protein RBM10, which interacts with JINR1 . RBM10 and JINR1 promote the proinflammatory transcription factor NF-κB activity, which is detrimental to cell survival.