Virus Genes

, Volume 55, Issue 5, pp 630–642 | Cite as

Upregulated expression of the antioxidant sestrin 2 identified by transcriptomic analysis of Japanese encephalitis virus-infected SH-SY5Y neuroblastoma cells

  • Michael CarrEmail author
  • Gabriel Gonzalez
  • Axel Martinelli
  • Christida E. Wastika
  • Kimihito Ito
  • Yasuko Orba
  • Michihito Sasaki
  • William W. Hall
  • Hirofumi Sawa
Original Paper


Japanese encephalitis virus (JEV) exerts a profound burden of viral encephalitis. We have investigated the differentially expressed transcripts in the neuronal transcriptome during JEV infection by RNA sequencing (RNA-Seq) of virus-infected SH-SY5Y human neuroblastoma cells. Gene ontology analysis revealed significant enrichment from two main pathways: endoplasmic reticulum (ER)-nucleus signaling (P value: 5.75E−18; false discovery rate [FDR] 3.11E−15) and the ER unfolded protein response (P value: 7.58E−18; FDR 3.11E−15). qPCR validation showed significant upregulation and differential expression (P < 0.01) of ER stress-signaling transcripts (SESN2, TRIB3, DDIT3, DDIT4, XBP1, and ATF4) at 24 h post-infection for both low (LN) and high (HN) neurovirulence JEV strains. Immunoblot analysis following JEV infection of SH-SY5Y cells showed an increase in levels of SESN2 protein following JEV infection. Similarly, Zika virus (MR766) infection of SH-SY5Y showed a titer-dependent increase in ER stress-signaling transcripts; however, this was absent or diminished for DDIT4 and ATF4, respectively, suggestive of differences in the induction of stress-response transcripts between flaviviruses. Interestingly, SLC7A11 and SLC3A2 mRNA were also both deregulated in JEV-infected SH-SY5Y cells and encode the two constituent subunits of the plasma membrane xCT amino acid antiporter that relieves oxidative stress by export of glutamate and import of cystine. Infection of SH-SY5Y and HEK293T cells by the JEV HN strain Sw/Mie/40/2004 lead to significant upregulation of the SLC7A11 mRNA to levels comparable to DDIT3. Our findings suggest upregulation of antioxidants including SESN2 and, also, the xCT antiporter occurs to counteract the oxidative stress elicited by JEV infection.


Japanese encephalitis virus Neuron RNA-Seq Sestrin xCT antiporter 



We are extremely grateful to Dr. Tomohiko Takashi from the National Institute of Infectious Diseases, Tokyo for the kind gift of the JEV strains and to Dr. Takashi Kimura (Hokkaido University) for rabbit anti-JEV hyperimmune sera. This study was supported in part by a grant to Dr. Michael Carr from the Japanese Society for the Promotion of Science (JSPS/KAKENHI) of Japan (16K08803). This study was also supported in part by grants to Professor Hirofumi Sawa for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Science, Sports and Technology (MEXT) of Japan (16H06429, 16H06431, 16K21723), grants from the Ministry of Education, Culture, Sports, Science and Technology; the Ministry of Health, Labour and Welfare, Japan (MEXT)/JSPS KAKENHI (16H05805).

Author contributions

All authors contributed to the study design. MC performed the experiments and GG and AM performed the bioinformatic analyses. All authors contributed to data analysis and the writing and editing of the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Research involving human participants or animals

This article does not contain any study involving either human participants or animals performed by any of the authors.

Supplementary material

11262_2019_1683_MOESM1_ESM.tif (1.3 mb)
Supplementary material 1 (TIFF 1310 kb) Supplementary material 1 (TIFF 1310 kb) Supplementary Figure 1. Immunofluorescence analysis of JEV-infected SH-SY5Y cells. SH-SY5Y neuroblastoma cells were mock-infected or infected with JEV HN strain at a MOI of 10, 25, 50 and 100 and were then fixed 24 hpi. The number of JEV-infected cells was examined by immunofluorescence using rabbit anti-JEV hyperimmune sera.
11262_2019_1683_MOESM2_ESM.tif (352 kb)
Supplementary material 2 (TIFF 351 kb) Supplementary material 2 (TIFF 351 kb) Supplementary Figure 2A. PCA and t-SNE analysis of the RNA-Seq data derived from the JEV-infected SH-SY5Y cells. Principal components analysis (PCA) plot of “Control” (mock-infected SH-SY5Y cells) versus “Infected” (JEV strain Sw/Mie/40/2004-infected) SH-SY5Y neuroblastoma cells at 24 hpi. Supplementary Figure 2B. T-distributed Stochastic Neighbour Embedding (t-SNE) plot of “Control” (mock-infected SH-SY5Y cells) versus “Infected” (JEV strain Sw/Mie/40/2004-infected) SH-SY5Y neuroblastoma cells at 24 hpi.
11262_2019_1683_MOESM3_ESM.tif (861 kb)
Supplementary material 3 (TIFF 861 kb) Supplementary material 3 (TIFF 861 kb) Supplementary Figure 3. CV and BCV of the of the RNA-Seq data derived from the JEV-infected SH-SY5Y cells. Coefficients of variation per gene (standard deviation / mean) among replicates for “control” (mock-infected) and “infected” (JEV-infected) samples. Horizontal and vertical axes show the coefficient of variation (CV) among control replicates and among infected replicates, respectively. A) CV for 15879 genes with reads in all replicates. B) CV for the 50 most significant DEGs. C) Biological coefficient of variation (BCV) for genes with expression (18078 genes). The common dispersion for the BCV was 0.005.
11262_2019_1683_MOESM4_ESM.tif (547 kb)
Supplementary material 4 (TIFF 547 kb) Supplementary material 4 (TIFF 547 kb) Supplementary Figure 4. Venn diagrams of the significantly up- and downregulated transcripts identified in the JEV-infected SH-SY5Y transcriptome. Differential expression analyses were performed by DESeq2 and EdgeR and the Venn diagrams are based on P values adjusted for false discovery rate.
11262_2019_1683_MOESM5_ESM.tif (10 mb)
Supplementary material 5 (TIFF 10219 kb) Supplementary material 5 (TIFF 10219 kb) Supplementary Figure 5. Immunofluorescence analysis of JEV-infected HEK293T cells. HEK293T cells were mock-infected or infected with JEV LN or HN strains at a MOI of 1, 10 and 25 and were then fixed 24 hpi. The number of JEV-infected cells was examined by immunofluorescence using rabbit anti-JEV hyperimmune sera.
11262_2019_1683_MOESM6_ESM.docx (12 kb)
Supplementary material 6 (DOCX 11 kb)


  1. 1.
    Takayama J. Japanese encephalitis. WHO, 2015Google Scholar
  2. 2.
    Yin Z, Wang X, Li L, Li H, Zhang X, Li J, Ning G, Li F, Liang X, Gao L, Liang X, Li Y (2015) Neurological sequelae of hospitalized Japanese encephalitis cases in Gansu province, China. Am J Trop Med Hyg 92:1125–1129. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Ghosh D, Basu A (2009) Japanese encephalitis-a pathological and clinical perspective. PLoS Negl Trop Dis 3:e437. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Solomon T (2004) Flavivirus encephalitis. N Engl J Med 351:370–378. CrossRefPubMedGoogle Scholar
  5. 5.
    Campbell GL, Hills SL, Fischer M, Jacobson JA, Hoke CH, Hombach JM, Marfin AA, Solomon T, Tsai TF, Tsu VD, Ginsburg AS (2011) Estimated global incidence of Japanese encephalitis: a systematic review. Bull World Health Organ 89(766–774):774A–774E. CrossRefGoogle Scholar
  6. 6.
    Myint KS, Kipar A, Jarman RG, Gibbons RV, Perng GC, Flanagan B, Mongkolsirichaikul D, Van Gessel Y, Solomon T (2014) Neuropathogenesis of Japanese encephalitis in a primate model. PLoS Negl Trop Dis 8:e2980. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Johnson RT, Burke DS, Elwell M, Leake CJ, Nisalak A, Hoke CH, Lorsomrudee W (1985) Japanese encephalitis: immunocytochemical studies of viral antigen and inflammatory cells in fatal cases. Ann Neurol 18:567–573. CrossRefPubMedGoogle Scholar
  8. 8.
    Desai A, Shankar SK, Ravi V, Chandramuki A, Gourie-Devi M (1995) Japanese encephalitis virus antigen in the human brain and its topographic distribution. Acta Neuropathol 89:368–373CrossRefPubMedGoogle Scholar
  9. 9.
    German AC, Myint KS, Mai NT, Pomeroy I, Phu NH, Tzartos J, Winter P, Collett J, Farrar J, Barrett A, Kipar A, Esiri MM, Solomon T (2006) A preliminary neuropathological study of Japanese encephalitis in humans and a mouse model. Trans R Soc Trop Med Hyg 100:1135–1145. CrossRefPubMedGoogle Scholar
  10. 10.
    Gupta N, Santhosh SR, Babu JP, Parida MM, Rao PV (2010) Chemokine profiling of Japanese encephalitis virus-infected mouse neuroblastoma cells by microarray and real-time RT-PCR: implication in neuropathogenesis. Virus Res 147:107–112. CrossRefPubMedGoogle Scholar
  11. 11.
    Trottier MD Jr, Palian BM, Reiss CS (2005) VSV replication in neurons is inhibited by type I IFN at multiple stages of infection. Virology 333:215–225CrossRefPubMedGoogle Scholar
  12. 12.
    Samuel MA, Diamond MS (2005) Alpha/beta interferon protects against lethal West Nile virus infection by restricting cellular tropism and enhancing neuronal survival. J Virol 79:13350–13361. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Daffis S, Samuel MA, Suthar MS, Gale M, Diamond MS (2008) Toll-like receptor 3 has a protective role against West Nile virus infection. J Virol 82:10349–10358. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Cho H, Proll SC, Szretter KJ, Katze MG, Gale M, Diamond MS (2013) Differential innate immune response programs in neuronal subtypes determine susceptibility to infection in the brain by positive-stranded RNA viruses. Nat Med 19(4):458. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Rosato PC, Leib DA (2015) Neuronal interferon signaling is required for protection against herpes simplex virus replication and pathogenesis. PLoS Pathog 11(1):456. CrossRefGoogle Scholar
  16. 16.
    Budanov AV, Sablina AA, Feinstein E, Koonin EV, Chumakov PM (2004) Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD. Science 304:596–600. CrossRefPubMedGoogle Scholar
  17. 17.
    Lee JH, Budanov AV, Park EJ, Birse R, Kim TE, Perkins GA, Ocorr K, Ellisman MH, Bodmer R, Bier E, Karin M (2010) Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies. Science 327:1223–1228. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124:471–484. CrossRefPubMedGoogle Scholar
  19. 19.
    Saxton RA, Sabatini DM (2017) mTOR signaling in growth, metabolism, and disease. Cell 168:960–976. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12:21–35. CrossRefPubMedGoogle Scholar
  21. 21.
    Lee JH, Budanov AV, Talukdar S, Park EJ, Park HL, Park HW, Bandyopadhyay G, Li N, Aghajan M, Jang I, Wolfe AM, Perkins GA, Ellisman MH, Bier E, Scadeng M, Foretz M, Viollet B, Olefsky J, Karin M (2012) Maintenance of metabolic homeostasis by Sestrin2 and Sestrin3. Cell Metab 16:311–321. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Budanov AV, Karin M (2008) p53 target genes Sestrin1 and Sestrin2 connect genotoxic stress and mTOR signaling. Cell 134:451–460. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Maiuri MC, Malik SA, Morselli E, Kepp O, Criollo A, Mouchel PL, Carnuccio R, Kroemer G (2009) Stimulation of autophagy by the p53 target gene Sestrin2. Cell Cycle 8:1571–1576. CrossRefPubMedGoogle Scholar
  24. 24.
    Sanli T, Linher-Melville K, Tsakiridis T, Singh G (2012) Sestrin2 modulates AMPK subunit expression and its response to ionizing radiation in breast cancer cells. PLoS ONE 7(1):789. CrossRefGoogle Scholar
  25. 25.
    Budanov AV, Shoshani T, Faerman A, Zelin E, Kamer I, Kalinski H, Gorodin S, Fishman A, Chajut A, Einat P, Skaliter R, Gudkov AV, Chumakov PM, Feinstein E (2002) Identification of a novel stress-responsive gene Hi95 involved in regulation of cell viability. Oncogene 21:6017–6031. CrossRefPubMedGoogle Scholar
  26. 26.
    Kim MJ, Bae SH, Ryu JC, Kwon Y, Oh JH, Kwon J, Moon JS, Kim K, Miyawaki A, Lee MG, Shin J, Kim YS, Kim CH, Ryter SW, Choi AMK, Rhee SG, Ryu JH, Yoon JH (2016) SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages. Autophagy 12:1272–1291. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Mutz KO, Heilkenbrinker A, Lonne M, Walter JG, Stahl F (2013) Transcriptome analysis using next-generation sequencing. Curr Opin Biotech 24:22–30. CrossRefPubMedGoogle Scholar
  28. 28.
    Yamaguchi Y, Nukui Y, Tajima S, Nerome R, Kato F, Watanabe H, Takasaki T, Kurane I (2011) An amino acid substitution (V3I) in the Japanese encephalitis virus NS4A protein increases its virulence in mice, but not its growth rate in vitro. J Gen Virol 92:1601–1606. CrossRefPubMedGoogle Scholar
  29. 29.
    Bray NL, Pimentel H, Melsted P, Pachter L (2016) Near-optimal probabilistic RNA-seq quantification. Nat Biotechnol 34:525–527. CrossRefPubMedGoogle Scholar
  30. 30.
    Liao Y, Smyth GK, Shi W (2013) The Subread aligner: fast, accurate and scalable read mapping by seed-and-vote. Nucleic Acids Res 41:e108. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Robinson MD, McCarthy DJ, Smyth GK (2010) edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26:139–140. CrossRefPubMedGoogle Scholar
  32. 32.
    Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Kimura T, Sasaki M, Okumura M, Kim E, Sawa H (2010) Flavivirus encephalitis: pathological aspects of mouse and other animal models. Vet Pathol 47:806–818. CrossRefPubMedGoogle Scholar
  34. 34.
    Gidalevitz T, Stevens F, Argon Y (2013) Orchestration of secretory protein folding by ER chaperones. Biochim Biophys Acta 1833:2410–2424. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Lin D, Liang Y, Zheng D, Chen Y, Jing X, Lei M, Zeng Z, Zhou T, Wu X, Peng S, Huang K, Yang L, Xiao S, Liu J, Tao E (2018) Novel biomolecular information in rotenone-induced cellular model of Parkinson’s disease. Gene 647:244–260. CrossRefPubMedGoogle Scholar
  36. 36.
    McLaughlin T, Falkowski M, Wang JJ, Zhang SX (2018) Molecular chaperone ERp29: a potential target for cellular protection in retinal and neurodegenerative diseases. Adv Exp Med Biol 1074:421–427. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Ma H, Dang Y, Wu Y, Jia G, Anaya E, Zhang J, Abraham S, Choi JG, Shi G, Qi L, Manjunath N, Wu H (2015) A CRISPR-based screen identifies genes essential for west-nile-virus-induced cell death. Cell Rep 12:673–683. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Hoshino T, Murao N, Namba T, Takehara M, Adachi H, Katsuno M, Sobue G, Matsushima T, Suzuki T, Mizushima T (2011) Suppression of Alzheimer’s disease-related phenotypes by expression of heat shock protein 70 in mice. J Neurosci 31:5225–5234. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Slodzinski H, Moran LB, Michael GJ, Wang B, Novoselov S, Cheetham ME, Pearce RKB, Graeber MB (2009) Homocysteine-induced endoplasmic reticulum protein (Herp) is up-regulated in parkinsonian substantia nigra and present in the core of Lewy bodies. Clin Neuropathol 28:333–343. CrossRefPubMedGoogle Scholar
  40. 40.
    Eletto D, Chevet E, Argon Y, Appenzeller-Herzog C (2014) Redox controls UPR to control redox. J Cell Sci 127:3649–3658. CrossRefPubMedGoogle Scholar
  41. 41.
    Jauhiainen A, Thomsen C, Strombom L, Grundevik P, Andersson C, Danielsson A, Andersson MK, Nerman O, Rorkvist L, Stahlberg A, Aman P (2012) Distinct cytoplasmic and nuclear functions of the stress induced protein DDIT3/CHOP/GADD153. PLoS ONE 7:e33208. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Nerome R, Tajima S, Takasaki T, Yoshida T, Kotaki A, Lim CK, Ito M, Sugiyama A, Yamauchi A, Yano T, Kameyama T, Morishita I, Kuwayama M, Ogawa T, Sahara K, Ikegaya A, Kanda M, Hosoya Y, Itokazu K, Onishi H, Chiya S, Yoshida Y, Tabei Y, Katsuki K, Tabata K, Harada S, Kurane I (2007) Molecular epidemiological analyses of Japanese encephalitis virus isolates from swine in Japan from 2002 to 2004. J Gen Virol 88:2762–2768. CrossRefPubMedGoogle Scholar
  43. 43.
    Lewerenz J, Hewett SJ, Huang Y, Lambros M, Gout PW, Kalivas PW, Massie A, Smolders I, Methner A, Pergande M, Smith SB, Ganapathy V, Maher P (2013) The cystine/glutamate antiporter system xc in health and disease: from molecular mechanisms to novel therapeutic opportunities. Antioxid Redox Sign 18:522–555. CrossRefGoogle Scholar
  44. 44.
    Shin CS, Mishra P, Watrous JD, Carelli V, D’Aurelio M, Jain M, Chan DC (2017) The glutamate/cystine xCT antiporter antagonizes glutamine metabolism and reduces nutrient flexibility. Nat Commun. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Pasha M, Eid AH, Eid AA, Gorin Y, Munusamy S (2017) Sestrin2 as a novel biomarker and therapeutic target for various diseases. Oxid Med Cell Longev. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Su HL, Liao CL, Lin YL (2002) Japanese encephalitis virus infection initiates endoplasmic reticulum stress and an unfolded protein response. J Virol 76:4162–4171CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Sharma M, Bhattacharyya S, Sharma KB, Chauhan S, Asthana S, Abdin MZ, Vrati S, Kalia M (2017) Japanese encephalitis virus activates autophagy through XBP1 and ATF6 ER stress sensors in neuronal cells. J Gen Virol 98:1027–1039. CrossRefPubMedGoogle Scholar
  48. 48.
    Soontornniyomkij V, Soontornniyomkij B, Moore DJ, Gouaux B, Masliah E, Tung S, Vinters HV, Grant I, Achim CL (2012) Antioxidant sestrin-2 redistribution to neuronal soma in human immunodeficiency virus-associated neurocognitive disorders. J Neuroimmune Pharmacol 7:579–590. CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Zhou D, Zhan C, Zhong Q, Li S (2013) Upregulation of sestrin-2 expression via P53 protects against 1-methyl-4-phenylpyridinium (MPP +) neurotoxicity. J Mol Neurosci 51:967–975. CrossRefPubMedGoogle Scholar
  50. 50.
    Rai N, Kumar R, Desai GR, Venugopalan G, Shekhar S, Chatterjee P, Tripathi M, Upadhyay AD, Dwivedi S, Dey AB, Dey S (2016) Relative alterations in blood-based levels of sestrin in alzheimer’s disease and mild cognitive impairment patients. J Alzheimers Dis 54:1147–1155. CrossRefPubMedGoogle Scholar
  51. 51.
    Pradhan S, Pandey N, Shashank S, Gupta RK, Mathur A (1999) Parkinsonism due to predominant involvement of substantia nigra in Japanese encephalitis. Neurology 53:1781–1786. CrossRefPubMedGoogle Scholar
  52. 52.
    Ogata A, Tashiro K (2000) Parkinsonism due to predominant involvement of substantia nigra in Japanese encephalitis. Neurology 55:602. CrossRefPubMedGoogle Scholar
  53. 53.
    Kumar A, Shaha C (2018) SESN2 facilitates mitophagy by helping Parkin translocation through ULK1 mediated Beclin1 phosphorylation. Sci Rep 8(1):615. CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605–608CrossRefPubMedGoogle Scholar
  55. 55.
    Tran SC, Pham TM, Nguyen LN, Park EM, Lim YS, Hwang SB (2016) Nonstructural 3 protein of hepatitis C virus modulates the tribbles homolog 3/AKT signaling pathway for persistent viral infection. J Virol 90:7231–7247. CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Mukherjee S, Singh N, Sengupta N, Fatima M, Seth P, Mahadevan A, Shankar SK, Bhattacharyya A, Basu A (2017) Japanese encephalitis virus induces human neural stem/progenitor cell death by elevating GRP78, PHB and hnRNPC through ER stress. Cell Death Dis 8(1):e2556. CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Giffin L, Yan F, Ben Major M, Damania B (2014) Modulation of kaposi’s sarcoma-associated herpesvirus interleukin-6 function by hypoxia-upregulated protein 1. J Virol 88:9429–9441. CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Tang HL, Hammack C, Ogden SC, Wen ZX, Qian XY, Li YJ, Yao B, Shin J, Zhang FR, Lee EM, Christian KM, Didier RA, Jin P, Song HJ, Ming GL (2016) Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell 18:587–590. CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Zhou Y, Wang X, Tzingounis AV, Danbolt NC, Larsson HP (2014) EAAT2 (GLT-1; slc1a2) glutamate transporters reconstituted in liposomes argues against heteroexchange being substantially faster than net uptake. J Neurosci 34:13472–13485. CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Nguyen D, Alavi MV, Kim KY, Kang T, Scott RT, Noh YH, Lindsey JD, Wissinger B, Ellisman MH, Weinreb RN, Perkins GA, Ju WK (2011) A new vicious cycle involving glutamate excitotoxicity, oxidative stress and mitochondrial dynamics. Cell Death Dis 2:e240. CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    de Groot J, Sontheimer H (2011) Glutamate and the biology of gliomas. Glia 59:1181–1189. CrossRefPubMedGoogle Scholar
  62. 62.
    Singh S, Khan AR, Gupta AK (2012) Role of glutathione in cancer pathophysiology and therapeutic interventions. J Exp Ther Oncol 9:303–316PubMedGoogle Scholar
  63. 63.
    Pal B (2018) Involvement of extrasynaptic glutamate in physiological and pathophysiological changes of neuronal excitability. Cell Mol Life Sci. CrossRefPubMedGoogle Scholar
  64. 64.
    Lewerenz J, Baxter P, Kassubek R, Albrecht P, Van Liefferinge J, Westhoff MA, Halatsch ME, Karpel-Massler G, Meakin PJ, Hayes JD, Aronica E, Smolders I, Ludolph AC, Methner A, Conrad M, Massie A, Hardingham GE, Maher P (2014) Phosphoinositide 3-kinases upregulate system Xc via eukaryotic initiation factor 2 alpha and activating transcription factor 4—A pathway active in glioblastomas and epilepsy. Antioxid Redox Signal 20:2907–2922. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education (GI-CoRE)Hokkaido UniversitySapporoJapan
  2. 2.National Virus Reference Laboratory, School of MedicineUniversity College DublinDublin 4Ireland
  3. 3.Division of Bioinformatics, Research Center for Zoonosis ControlHokkaido UniversitySapporoJapan
  4. 4.Division of Molecular Pathobiology, Research Center for Zoonosis ControlHokkaido UniversitySapporoJapan
  5. 5.Global Virus NetworkBaltimoreUSA

Personalised recommendations