1887

Abstract

Japanese encephalitis virus (JEV) infection-induced encephalitis causes extensive death or long-term neurological damage, especially among children, in south and south-east Asia. Infection of mammalian cells has shown induction of an unfolded protein response (UPR), presumably leading to programmed cell death or apoptosis of the host cells. UPR, a cellular response to accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) lumen, is initiated by three ER-lumen-resident sensors (PERK, IRE1 and ATF6), and involves transcriptional and translational regulation of the expression of several genes. The sensor IRE1 possesses an intrinsic RNase activity, activated through homo-dimerization and autophosphorylation during UPR. Activated IRE1 performs cytoplasmic cleavage of transcripts, thus facilitating synthesis of XBP1S transcription factor, in addition to cleavage of a cohort of cellular transcripts, the later initiating the regulated IRE1-dependent decay (RIDD) pathway. In this study, we report the initiation of the RIDD pathway in JEV-infected mouse neuroblastoma cells (Neuro2a) and its effect on viral infection. Activation of the RIDD pathway led to degradation of known mouse cell target transcripts without showing any effect on JEV RNA despite the fact that both when biochemically purified showed significant enrichment in ER membrane-enriched fractions. Additionally, inhibition of the IRE1 RNase activity by STF083010, a specific drug, diminished viral protein levels and reduced the titre of the virus produced from infected Neuro2a cells. The results present evidence for the first report of a beneficial effect of RIDD activation on the viral life cycle.

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2014-01-01
2019-10-15
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References

  1. Akaike T., Maeda H.. ( 2000; ). Nitric oxide and virus infection. . Immunology 101:, 300–308. [CrossRef] [PubMed]
    [Google Scholar]
  2. Ambrose R. L., Mackenzie J. M.. ( 2011; ). West Nile virus differentially modulates the unfolded protein response to facilitate replication and immune evasion. . J Virol 85:, 2723–2732. [CrossRef] [PubMed]
    [Google Scholar]
  3. Biswas S. M., Kar S., Singh R., Chakraborty D., Vipat V., Raut C. G., Mishra A. C., Gore M. M., Ghosh D.. ( 2010; ). Immunomodulatory cytokines determine the outcome of Japanese encephalitis virus infection in mice. . J Med Virol 82:, 304–310. [CrossRef] [PubMed]
    [Google Scholar]
  4. Blobel G., Dobberstein B.. ( 1975a; ). Transfer of proteins across membranes. I. Presence of proteolytically processed and unprocessed nascent immunoglobulin light chains on membrane-bound ribosomes of murine myeloma. . J Cell Biol 67:, 835–851. [CrossRef] [PubMed]
    [Google Scholar]
  5. Blobel G., Dobberstein B.. ( 1975b; ). Transfer of proteins across membranes. II. Reconstitution of functional rough microsomes from heterologous components. . J Cell Biol 67:, 852–862. [CrossRef] [PubMed]
    [Google Scholar]
  6. Burnett H. F., Audas T. E., Liang G., Lu R. R.. ( 2012; ). Herpes simplex virus-1 disarms the unfolded protein response in the early stages of infection. . Cell Stress Chaperones 17:, 473–483. [CrossRef] [PubMed]
    [Google Scholar]
  7. Calfon M., Zeng H., Urano F., Till J. H., Hubbard S. R., Harding H. P., Clark S. G., Ron D.. ( 2002; ). IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. . Nature 415:, 92–96. [CrossRef] [PubMed]
    [Google Scholar]
  8. Chen Q., Jagannathan S., Reid D. W., Zheng T., Nicchitta C. V.. ( 2011; ). Hierarchical regulation of mRNA partitioning between the cytoplasm and the endoplasmic reticulum of mammalian cells. . Mol Biol Cell 22:, 2646–2658. [CrossRef] [PubMed]
    [Google Scholar]
  9. Fernandez-Garcia M. D., Mazzon M., Jacobs M., Amara A.. ( 2009; ). Pathogenesis of flavivirus infections: using and abusing the host cell. . Cell Host Microbe 5:, 318–328. [CrossRef] [PubMed]
    [Google Scholar]
  10. Ghoshal A., Das S., Ghosh S., Mishra M. K., Sharma V., Koli P., Sen E., Basu A.. ( 2007; ). Proinflammatory mediators released by activated microglia induces neuronal death in Japanese encephalitis. . Glia 55:, 483–496. [CrossRef] [PubMed]
    [Google Scholar]
  11. Goodman A. G., Fornek J. L., Medigeshi G. R., Perrone L. A., Peng X., Dyer M. D., Proll S. C., Knoblaugh S. E., Carter V. S.. & other authors ( 2009; ). P58(IPK): a novel “CIHD” member of the host innate defense response against pathogenic virus infection. . PLoS Pathog 5:, e1000438. [CrossRef] [PubMed]
    [Google Scholar]
  12. Guo F., Lin E. A., Liu P., Lin J., Liu C.. ( 2010; ). XBP1U inhibits the XBP1S-mediated upregulation of the iNOS gene expression in mammalian ER stress response. . Cell Signal 22:, 1818–1828. [CrossRef] [PubMed]
    [Google Scholar]
  13. Hetz C.. ( 2012; ). The unfolded protein response: controlling cell fate decisions under ER stress and beyond. . Nat Rev Mol Cell Biol 13:, 89–102.[PubMed]
    [Google Scholar]
  14. Holden P., Horton W. A.. ( 2009; ). Crude subcellular fractionation of cultured mammalian cell lines. . BMC Res Notes 2:, 243. [CrossRef] [PubMed]
    [Google Scholar]
  15. Hollien J., Weissman J. S.. ( 2006; ). Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. . Science 313:, 104–107. [CrossRef] [PubMed]
    [Google Scholar]
  16. Hollien J., Lin J. H., Li H., Stevens N., Walter P., Weissman J. S.. ( 2009; ). Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. . J Cell Biol 186:, 323–331. [CrossRef] [PubMed]
    [Google Scholar]
  17. Huang J. L., Lin H. T., Wang Y. M., Weng M. H., Ji D. D., Kuo M. D., Liu H. W., Lin C. S.. ( 2004; ). Sensitive and specific detection of strains of Japanese encephalitis virus using a one-step TaqMan RT-PCR technique. . J Med Virol 74:, 589–596. [CrossRef] [PubMed]
    [Google Scholar]
  18. Lee A. H., Iwakoshi N. N., Glimcher L. H.. ( 2003; ). XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. . Mol Cell Biol 23:, 7448–7459. [CrossRef] [PubMed]
    [Google Scholar]
  19. Lerner R. S., Seiser R. M., Zheng T., Lager P. J., Reedy M. C., Keene J. D., Nicchitta C. V.. ( 2003; ). Partitioning and translation of mRNAs encoding soluble proteins on membrane-bound ribosomes. . RNA 9:, 1123–1137. [CrossRef] [PubMed]
    [Google Scholar]
  20. Lin K. C., Chang H. L., Chang R. Y.. ( 2004; ). Accumulation of a 3′-terminal genome fragment in Japanese encephalitis virus-infected mammalian and mosquito cells. . J Virol 78:, 5133–5138. [CrossRef] [PubMed]
    [Google Scholar]
  21. Medigeshi G. R., Lancaster A. M., Hirsch A. J., Briese T., Lipkin W. I., Defilippis V., Früh K., Mason P. W., Nikolich-Zugich J., Nelson J. A.. ( 2007; ). West Nile virus infection activates the unfolded protein response, leading to CHOP induction and apoptosis. . J Virol 81:, 10849–10860. [CrossRef] [PubMed]
    [Google Scholar]
  22. Merquiol E., Uzi D., Mueller T., Goldenberg D., Nahmias Y., Xavier R. J., Tirosh B., Shibolet O.. ( 2011; ). HCV causes chronic endoplasmic reticulum stress leading to adaptation and interference with the unfolded protein response. . PLoS ONE 6:, e24660. [CrossRef] [PubMed]
    [Google Scholar]
  23. Papandreou I., Denko N. C., Olson M., Van Melckebeke H., Lust S., Tam A., Solow-Cordero D. E., Bouley D. M., Offner F.. & other authors ( 2011; ). Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma. . Blood 117:, 1311–1314. [CrossRef] [PubMed]
    [Google Scholar]
  24. Peña J., Harris E.. ( 2011; ). Dengue virus modulates the unfolded protein response in a time-dependent manner. . J Biol Chem 286:, 14226–14236. [CrossRef] [PubMed]
    [Google Scholar]
  25. Pijlman G. P., Funk A., Kondratieva N., Leung J., Torres S., van der Aa L., Liu W. J., Palmenberg A. C., Shi P. Y.. & other authors ( 2008; ). A highly structured, nuclease-resistant, noncoding RNA produced by flaviviruses is required for pathogenicity. . Cell Host Microbe 4:, 579–591. [CrossRef] [PubMed]
    [Google Scholar]
  26. Rice C. M.. ( 1996; ). Flaviviridae: the viruses and their replication. . In Fields Virology, pp. 931–959. Edited by Fields B. N., Knipe D. M., Howley P. M... Philadelphia, PA:: Lippincott-Raven;.
    [Google Scholar]
  27. Saeed M., Suzuki R., Watanabe N., Masaki T., Tomonaga M., Muhammad A., Kato T., Matsuura Y., Watanabe H.. & other authors ( 2011; ). Role of the endoplasmic reticulum-associated degradation (ERAD) pathway in degradation of hepatitis C virus envelope proteins and production of virus particles. . J Biol Chem 286:, 37264–37273. [CrossRef] [PubMed]
    [Google Scholar]
  28. Scherbik S. V., Paranjape J. M., Stockman B. M., Silverman R. H., Brinton M. A.. ( 2006; ). RNase L plays a role in the antiviral response to West Nile virus. . J Virol 80:, 2987–2999. [CrossRef] [PubMed]
    [Google Scholar]
  29. Schröder M., Kaufman R. J.. ( 2005; ). ER stress and the unfolded protein response. . Mutat Res 569:, 29–63. [CrossRef] [PubMed]
    [Google Scholar]
  30. Sheth U., Parker R.. ( 2003; ). Decapping and decay of messenger RNA occur in cytoplasmic processing bodies. . Science 300:, 805–808. [CrossRef] [PubMed]
    [Google Scholar]
  31. Su H. L., Liao C. L., Lin Y. L.. ( 2002; ). Japanese encephalitis virus infection initiates endoplasmic reticulum stress and an unfolded protein response. . J Virol 76:, 4162–4171. [CrossRef] [PubMed]
    [Google Scholar]
  32. Swarup V., Das S., Ghosh S., Basu A.. ( 2007; ). Tumor necrosis factor receptor-1-induced neuronal death by TRADD contributes to the pathogenesis of Japanese encephalitis. . J Neurochem 103:, 771–783. [CrossRef] [PubMed]
    [Google Scholar]
  33. Umareddy I., Pluquet O., Wang Q. Y., Vasudevan S. G., Chevet E., Gu F.. ( 2007; ). Dengue virus serotype infection specifies the activation of the unfolded protein response. . Virol J 4:, 91. [CrossRef] [PubMed]
    [Google Scholar]
  34. Urosevic N., van Maanen M., Mansfield J. P., Mackenzie J. S., Shellam G. R.. ( 1997; ). Molecular characterization of virus-specific RNA produced in the brains of flavivirus-susceptible and -resistant mice after challenge with Murray Valley encephalitis virus. . J Gen Virol 78:, 23–29.[PubMed]
    [Google Scholar]
  35. Vrati S., Agarwal V., Malik P., Wani S. A., Saini M.. ( 1999; ). Molecular characterization of an Indian isolate of Japanese encephalitis virus that shows an extended lag phase during growth. . J Gen Virol 80:, 1665–1671.[PubMed]
    [Google Scholar]
  36. Yanagitani K., Imagawa Y., Iwawaki T., Hosoda A., Saito M., Kimata Y., Kohno K.. ( 2009; ). Cotranslational targeting of XBP1 protein to the membrane promotes cytoplasmic splicing of its own mRNA. . Mol Cell 34:, 191–200. [CrossRef] [PubMed]
    [Google Scholar]
  37. Yoshida H., Matsui T., Yamamoto A., Okada T., Mori K.. ( 2001; ). XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. . Cell 107:, 881–891. [CrossRef] [PubMed]
    [Google Scholar]
  38. Yu C. Y., Hsu Y. W., Liao C. L., Lin Y. L.. ( 2006; ). Flavivirus infection activates the XBP1 pathway of the unfolded protein response to cope with endoplasmic reticulum stress. . J Virol 80:, 11868–11880. [CrossRef] [PubMed]
    [Google Scholar]
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