1887

Abstract

Endoplasmic reticulum (ER) stress and autophagy are key cellular responses to RNA virus infection. Recent studies have shown that Japanese encephalitis virus (JEV)-induced autophagy negatively influences virus replication in mouse neuronal cells and embryonic fibroblasts, and delays virus-induced cell death. Here, we evaluated the role of ER stress pathways in inducing autophagy during JEV infection. We observed that JEV infection of neuronal cells led to activation of all three sensors of ER stress mediated by eIF2α/PERK, IRE1/XBP1 and ATF6. The kinetics of autophagy induction as monitored by levels of SQSTM1 and LC3-II paralleled activation of ER stress. Inhibition of the eIF2α/PERK pathway by siRNA-mediated depletion of proteins and by the PERK inhibitor had no effect on autophagy and JEV replication. However, depletion of XBP1 and ATF6, alone or in combination, prevented autophagy induction and significantly enhanced JEV-induced cell death. JEV-infected cells depleted of XBP1 or ATF6 showed reduced transcription of ER chaperones, ERAD components and autophagy genes, resulting in reduced protein levels of the crucial autophagy effectors ATG3 and BECLIN-1. Conversely, pharmacological induction of ER stress in JEV-infected cells further enhanced autophagy and reduced virus titres. Our study thus demonstrates that a crucial link exists between the ER stress pathways and autophagy in virus-infected cells, and that these processes are highly regulated during virus infection.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.000792
2017-05-01
2019-12-11
Loading full text...

Full text loading...

/deliver/fulltext/jgv/98/5/1027.html?itemId=/content/journal/jgv/10.1099/jgv.0.000792&mimeType=html&fmt=ahah

References

  1. Lessler J, Chaisson LH, Kucirka LM, Bi Q, Grantz K et al. Assessing the global threat from Zika virus. Science 2016;353:aaf8160 [CrossRef][PubMed]
    [Google Scholar]
  2. Daep CA, Muñoz-Jordán JL, Eugenin EA. Flaviviruses, an expanding threat in public health: focus on dengue, West Nile, and Japanese encephalitis virus. J Neurovirol 2014;20:539–560 [CrossRef][PubMed]
    [Google Scholar]
  3. Dash AP, Bhatia R, Sunyoto T, Mourya DT, Emerging MDT. Emerging and re-emerging arboviral diseases in Southeast Asia. J Vector Borne Dis 2013;50:77–84[PubMed]
    [Google Scholar]
  4. Nain M, Abdin MZ, Kalia M, Vrati S. Japanese encephalitis virus invasion of cell: allies and alleys. Rev Med Virol 2016;26:129–141 [CrossRef][PubMed]
    [Google Scholar]
  5. Tiwari S, Singh RK, Tiwari R, Dhole TN. Japanese encephalitis: a review of the Indian perspective. Braz J Infect Dis 2012;16:564–573 [CrossRef][PubMed]
    [Google Scholar]
  6. Singh A, Mitra M, Sampath G, Venugopal P, Rao JV et al. A Japanese encephalitis vaccine from India induces durable and cross-protective immunity against temporally and spatially wide-ranging global field strains. J Infect Dis 2015;212:715–725 [CrossRef][PubMed]
    [Google Scholar]
  7. Vashishtha VM, Ramachandran VG. Vaccination policy for Japanese encephalitis in India: tread with caution!. Indian Pediatr 2015;52:837–839 [CrossRef][PubMed]
    [Google Scholar]
  8. Ambrose RL, Mackenzie JM. West Nile virus differentially modulates the unfolded protein response to facilitate replication and immune evasion. J Virol 2011;85:2723–2732 [CrossRef][PubMed]
    [Google Scholar]
  9. Peña J, Harris E. Dengue virus modulates the unfolded protein response in a time-dependent manner. J Biol Chem 2011;286:14226–14236 [CrossRef][PubMed]
    [Google Scholar]
  10. Su HL, Liao CL, Lin YL. Japanese encephalitis virus infection initiates endoplasmic reticulum stress and an unfolded protein response. J Virol 2002;76:4162–4171[PubMed][CrossRef]
    [Google Scholar]
  11. Umareddy I, Pluquet O, Wang QY, Vasudevan SG, Chevet E et al. Dengue virus serotype infection specifies the activation of the unfolded protein response. Virol J 2007;4:91 [CrossRef][PubMed]
    [Google Scholar]
  12. Harding HP, Zhang Y, Ron D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 1999;397:271–274 [CrossRef][PubMed]
    [Google Scholar]
  13. Shi Y, Vattem KM, Sood R, An J, Liang J et al. Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Mol Cell Biol 1998;18:7499–7509 [CrossRef][PubMed]
    [Google Scholar]
  14. Zhan Q, Lord KA, Alamo I, Hollander MC, Carrier F et al. The Gadd and MyD genes define a novel set of mammalian genes encoding acidic proteins that synergistically suppress cell growth. Mol Cell Biol 1994;14:2361–2371 [CrossRef][PubMed]
    [Google Scholar]
  15. Zinszner H, Kuroda M, Wang X, Batchvarova N, Lightfoot RT et al. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev 1998;12:982–995 [CrossRef][PubMed]
    [Google Scholar]
  16. Hollien J, Weissman JS. Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science 2006;313:104–107 [CrossRef][PubMed]
    [Google Scholar]
  17. Lee K, Tirasophon W, Shen X, Michalak M, Prywes R et al. IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. Genes Dev 2002;16:452–466 [CrossRef][PubMed]
    [Google Scholar]
  18. Ogata M, Hino S, Saito A, Morikawa K, Kondo S et al. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 2006;26:9220–9231 [CrossRef][PubMed]
    [Google Scholar]
  19. Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 2001;107:881–891 [CrossRef][PubMed]
    [Google Scholar]
  20. Haze K, Yoshida H, Yanagi H, Yura T, Mori K. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell 1999;10:3787–3799 [CrossRef][PubMed]
    [Google Scholar]
  21. Lee AH, Iwakoshi NN, Glimcher LH. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol 2003;23:7448–7459 [CrossRef][PubMed]
    [Google Scholar]
  22. Yamamoto K, Sato T, Matsui T, Sato M, Okada T et al. Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6α and XBP1. Dev Cell 2007;13:365–376 [CrossRef][PubMed]
    [Google Scholar]
  23. Shoulders MD, Ryno LM, Genereux JC, Moresco JJ, Tu PG, Pg T et al. Stress-independent activation of XBP1s and/or ATF6 reveals three functionally diverse ER proteostasis environments. Cell Rep 2013;3:1279–1292 [CrossRef][PubMed]
    [Google Scholar]
  24. Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 2012;13:89–102 [CrossRef][PubMed]
    [Google Scholar]
  25. Mizushima N. Autophagy: process and function. Genes Dev 2007;21:2861–2873 [CrossRef][PubMed]
    [Google Scholar]
  26. Heaton NS, Randall G. Dengue virus-induced autophagy regulates lipid metabolism. Cell Host Microbe 2010;8:422–432 [CrossRef][PubMed]
    [Google Scholar]
  27. Jin R, Zhu W, Cao S, Chen R, Jin H et al. Japanese encephalitis virus activates autophagy as a viral immune evasion strategy. PLoS One 2013;8:e52909 [CrossRef][PubMed]
    [Google Scholar]
  28. Jordan TX, Randall G. Manipulation or capitulation: virus interactions with autophagy. Microbes Infect 2012;14:126–139 [CrossRef][PubMed]
    [Google Scholar]
  29. Moy RH, Gold B, Molleston JM, Schad V, Yanger K et al. Antiviral autophagy restricts Rift Valley fever virus infection and is conserved from flies to mammals. Immunity 2014;40:51–65 [CrossRef][PubMed]
    [Google Scholar]
  30. Orvedahl A, Macpherson S, Sumpter R, Tallóczy Z, Zou Z et al. Autophagy protects against Sindbis virus infection of the central nervous system. Cell Host Microbe 2010;7:115–127 [CrossRef][PubMed]
    [Google Scholar]
  31. Sharma M, Bhattacharyya S, Nain M, Kaur M, Sood V et al. Japanese encephalitis virus replication is negatively regulated by autophagy and occurs on LC3-I- and EDEM1-containing membranes. Autophagy 2014;10:1637–1651 [CrossRef][PubMed]
    [Google Scholar]
  32. Yordy B, Iijima N, Huttner A, Leib D, Iwasaki A. A neuron-specific role for autophagy in antiviral defense against herpes simplex virus. Cell Host Microbe 2012;12:334–345 [CrossRef][PubMed]
    [Google Scholar]
  33. Li JK, Liang JJ, Liao CL, Lin YL. Autophagy is involved in the early step of Japanese encephalitis virus infection. Microbes Infect 2012;14:159–168 [CrossRef][PubMed]
    [Google Scholar]
  34. Ambrose RL, Mackenzie JM. ATF6 signaling is required for efficient West Nile virus replication by promoting cell survival and inhibition of innate immune responses. J Virol 2013;87:2206–2214 [CrossRef][PubMed]
    [Google Scholar]
  35. Medigeshi GR, Lancaster AM, Hirsch AJ, Briese T, Lipkin WI et al. West Nile virus infection activates the unfolded protein response, leading to CHOP induction and apoptosis. J Virol 2007;81:10849–10860 [CrossRef][PubMed]
    [Google Scholar]
  36. Wang J, Kang R, Huang H, Xi X, Wang B et al. Hepatitis C virus core protein activates autophagy through EIF2AK3 and ATF6 UPR pathway-mediated MAP1LC3B and ATG12 expression. Autophagy 2014;10:766–784 [CrossRef][PubMed]
    [Google Scholar]
  37. Yu C, Achazi K, Niedrig M. Tick-borne encephalitis virus triggers inositol-requiring enzyme 1 (IRE1) and transcription factor 6 (ATF6) pathways of unfolded protein response. Virus Res 2013;178:471–477 [CrossRef][PubMed]
    [Google Scholar]
  38. Yu CY, Hsu YW, Liao CL, Lin YL. Flavivirus infection activates the XBP1 pathway of the unfolded protein response to cope with endoplasmic reticulum stress. J Virol 2006;80:11868–11880 [CrossRef][PubMed]
    [Google Scholar]
  39. Bhattacharyya S, Sen U, Vrati S. Regulated IRE1-dependent decay pathway is activated during Japanese encephalitis virus-induced unfolded protein response and benefits viral replication. J Gen Virol 2014;95:71–79 [CrossRef][PubMed]
    [Google Scholar]
  40. Datan E, Roy SG, Germain G, Zali N, Mclean JE et al. Dengue-induced autophagy, virus replication and protection from cell death require ER stress (PERK) pathway activation. Cell Death Dis 2016;7:e2127 [CrossRef][PubMed]
    [Google Scholar]
  41. Mclean JE, Wudzinska A, Datan E, Quaglino D, Zakeri Z. Flavivirus NS4A-induced autophagy protects cells against death and enhances virus replication. J Biol Chem 2011;286:22147–22159 [CrossRef][PubMed]
    [Google Scholar]
  42. Carpenter JE, Jackson W, Benetti L, Grose C. Autophagosome formation during varicella-zoster virus infection following endoplasmic reticulum stress and the unfolded protein response. J Virol 2011;85:9414–9424 [CrossRef][PubMed]
    [Google Scholar]
  43. Hou L, Ge X, Xin L, Zhou L, Guo X et al. Nonstructural proteins 2C and 3D are involved in autophagy as induced by the encephalomyocarditis virus. Virol J 2014;11:156 [CrossRef][PubMed]
    [Google Scholar]
  44. Lv S, Sun EC, Xu QY, Zhang JK, Wu DL. Endoplasmic reticulum stress-mediated autophagy contributes to bluetongue virus infection via the PERK-eIF2α pathway. Biochem Biophys Res Commun 2015;466:406–412 [CrossRef][PubMed]
    [Google Scholar]
  45. Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 2016;12:1–222 [CrossRef][PubMed]
    [Google Scholar]
  46. Calfon M, Zeng H, Urano F, Till JH, Hubbard SR et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 2002;415:92–96 [CrossRef][PubMed]
    [Google Scholar]
  47. Urano F, Wang X, Bertolotti A, Zhang Y, Chung P et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 2000;287:664–666 [CrossRef][PubMed]
    [Google Scholar]
  48. Chen X, Shen J, Prywes R. The luminal domain of ATF6 senses endoplasmic reticulum (ER) stress and causes translocation of ATF6 from the ER to the Golgi. J Biol Chem 2002;277:13045–13052 [CrossRef][PubMed]
    [Google Scholar]
  49. Shen J, Chen X, Hendershot L, Prywes R. ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev Cell 2002;3:99–111 [CrossRef][PubMed]
    [Google Scholar]
  50. Acosta-Alvear D, Zhou Y, Blais A, Tsikitis M, Lents NH et al. XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks. Mol Cell 2007;27:53–66 [CrossRef][PubMed]
    [Google Scholar]
  51. Bhattacharyya S, Vrati S. The Malat1 long non-coding RNA is upregulated by signalling through the PERK axis of unfolded protein response during flavivirus infection. Sci Rep 2015;5:17794 [CrossRef][PubMed]
    [Google Scholar]
  52. Wiseman RL, Zhang Y, Lee KP, Harding HP, Haynes CM et al. Flavonol activation defines an unanticipated ligand-binding site in the kinase-RNase domain of IRE1. Mol Cell 2010;38:291–304 [CrossRef][PubMed]
    [Google Scholar]
  53. Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 2007;8:519–529 [CrossRef][PubMed]
    [Google Scholar]
  54. Schröder M, Kaufman RJ. The mammalian unfolded protein response. Annu Rev Biochem 2005;74:739–789 [CrossRef][PubMed]
    [Google Scholar]
  55. Tallóczy Z, Jiang W, Virgin HW, Leib DA, Scheuner D et al. Regulation of starvation- and virus-induced autophagy by the eIF2α kinase signaling pathway. Proc Natl Acad Sci USA 2002;99:190–195 [CrossRef][PubMed]
    [Google Scholar]
  56. Joubert PE, Werneke SW, de La Calle C, Guivel-Benhassine F, Giodini A et al. Chikungunya virus-induced autophagy delays caspase-dependent cell death. J Exp Med 2012;209:1029–1047 [CrossRef][PubMed]
    [Google Scholar]
  57. Novoa I, Zeng H, Harding HP, Ron D. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2α. J Cell Biol 2001;153:1011–1022 [CrossRef][PubMed]
    [Google Scholar]
  58. Smith JA. A new paradigm: innate immune sensing of viruses via the unfolded protein response. Front Microbiol 2014;5:222 [CrossRef][PubMed]
    [Google Scholar]
  59. Smith JA, Turner MJ, Delay ML, Klenk EI, Sowders DP et al. Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN-β induction via X-box binding protein 1. Eur J Immunol 2008;38:1194–1203 [CrossRef][PubMed]
    [Google Scholar]
  60. Rao J, Yue S, Fu Y, Zhu J, Wang X et al. ATF6 mediates a pro-inflammatory synergy between ER stress and TLR activation in the pathogenesis of liver ischemia-reperfusion injury. Am J Transplant 2014;14:1552–1561 [CrossRef][PubMed]
    [Google Scholar]
  61. Vrati S, Agarwal V, Malik P, Wani SA, Saini M. Molecular characterization of an Indian isolate of Japanese encephalitis virus that shows an extended lag phase during growth. J Gen Virol 1999;80:1665–1671 [CrossRef][PubMed]
    [Google Scholar]
  62. Wang Y, Shen J, Arenzana N, Tirasophon W, Kaufman RJ et al. Activation of ATF6 and an ATF6 DNA binding site by the endoplasmic reticulum stress response. J Biol Chem 2000;275:27013–27020 [CrossRef][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.000792
Loading
/content/journal/jgv/10.1099/jgv.0.000792
Loading

Data & Media loading...

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error