Quantitative phosphoproteomic analysis identifies the critical role of JNK1 in neuroinflammation induced by Japanese encephalitis virus
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.
Abstract
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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Supplementary Material
Summary
Fig. S1. Expression of inflammatory cytokines in JEV-infected U251 cells.
Fig. S2. Protein-protein interaction network constructed from the phosphoproteins regulated by JEV infection of U251 cells.
Fig. S3. Representative MS of phosphorylated peptides of AKT1, PRKACA, and TP53.
Table S1. Quantification of phosphopeptides detected by LC-MS/MS.
Table S2. Differentially regulated phosphopeptides in response to JEV infection.
Table S3. GO and KEGG pathway analysis of the up-regulated phosphoproteome of JEV-infected U251 cells.
Table S4. GO and KEGG pathway analysis of the down-regulated phosphoproteome of JEV-infected U251 cells.
Table S5. Phosphoproteins in the interaction network of JEV-infected U251 cells.
Table S6. Differentially regulated phosphoproteins that are shared between cells infected with JEV or WNV.
Table S7. Prediction of JEV-responsive kinases by using the GPS.
Table S8. Overrepresented motifs in the up-regulated phosphoproteins in JEV-infected cells.
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Published In
Science Signaling
Volume 9 | Issue 448
October 2016
October 2016
Copyright
Copyright © 2016, American Association for the Advancement of Science.
Submission history
Received: 21 February 2016
Accepted: 15 September 2016
Acknowledgments
We thank other members of the State Key Laboratory of Agricultural Microbiology for help and fruitful discussions. Funding: This work was supported by the National Key Research and Development Program of China (2016YFD05004007), the National Natural Science Foundation of China (31502065 and 31572517), China Postdoctoral Science Foundation (2015M582245), the Special Fund for Agro-scientific Research in the Public Interest (201203082), the 948 project (2011-G24), the Fundamental Research Funds for the Central Universities (2013PY051, 2662016Q003, and 2662015PY083), and the Program of Introducing Talents of Discipline to Universities (B12005). Author contributions: J.Y., W.H., and Z.C. performed most of the experiments. H.Z. performed biochemical analysis. B.Z. and D.Z. performed in vivo experiments. J.Y., Y.W., and S.C. planned experiments and analyzed results. J.Y. and U.A. wrote the paper, with contribution from the rest of the authors. S.C., H.C., Z.F.F., and Z.L. conceived and supervised the project. Competing interests: The authors declare that they have no competing financial interests. Data and materials availability: Proteomic data have been submitted to the Proteomics Identification Database (accession number: PXD004976).
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