Research ArticleViral Infection

Quantitative phosphoproteomic analysis identifies the critical role of JNK1 in neuroinflammation induced by Japanese encephalitis virus

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Science Signaling  04 Oct 2016:
Vol. 9, Issue 448, pp. ra98
DOI: 10.1126/scisignal.aaf5132

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Halting viral encephalitis

Japanese encephalitis virus (JEV) is a member of the mosquito-borne flavivirus family, which includes hepatitis C virus, West Nile virus, yellow fever virus, Zika virus, and dengue virus. Common in Asia and Australia, JEV crosses the blood-brain barrier and produces massive neuroinflammation, which causes neuronal damage and death, such that even people who survive the infection have long-term neurological impairment. Ye et al. took a phosphoproteomic approach and identified several kinase pathways induced by JEV infection of cultured human glial cells. Substrates of the JNK pathway were the most overrepresented in the data set, and treating glial cells in culture with a JNK inhibitor reduced the JEV infection–induced stimulation of inflammatory cytokines. This same inhibitor prevented JEV lethality in mice, which was associated with a decrease in neuroinflammation (reduced astrocytosis and microgliosis), as well as less neuronal injury (reduced apoptotic neurons). These results may prove useful in treating JEV and other neurotropic viruses of this or other viral families.


Japanese encephalitis virus (JEV) is the leading cause of epidemic encephalitis worldwide. The pathogenesis of JEV is linked to a robust inflammatory response in the central nervous system (CNS). Glial cells are the resident immune cells in the CNS and represent critical effectors of CNS inflammation. To obtain a global overview of signaling events in glial cells during JEV infection, we conducted phosphoproteomics profiling of a JEV-infected glial cell line. We identified 1816 phosphopeptides, corresponding to 1264 proteins, that exhibited a change in phosphorylation status upon JEV infection. Bioinformatics analysis revealed that these proteins were predominantly related to transcription regulation, signal transduction, the cell cycle, and the cytoskeleton. Kinase substrate motif revealed that substrates for c-Jun N-terminal kinase 1 (JNK1) were the most overrepresented, along with evidence of increased AKT1 and protein kinase A (PKA) signaling. Pharmacological inhibition of JNK, AKT, or PKA reduced the inflammatory response of cultured glial cells infected with JEV, as did knockdown of JNK1 or its target JUN. JEV genomic RNA was sufficient to activate JNK1 signaling in cultured glial cells. Of potential clinical relevance, we showed that inhibition of JNK signaling significantly attenuated the production of inflammatory cytokines in the brain and reduced lethality in JEV-infected mice, thereby suggesting that JNK signaling is a potential therapeutic target for the management of Japanese encephalitis.

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