Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Translation inhibition and stress granules in the antiviral immune response

Key Points

  • Stress granules form when cells sense stress and rapidly arrest protein synthesis. Double-stranded RNA-activated protein kinase (PKR) is the main sensor protein that detects virus infection and phosphorylates eukaryotic translation initiation factor 2α (eIF2α) to stall bulk protein synthesis and elicit the formation of stress granules.

  • Many viruses have evolved diverse mechanisms to prevent the formation of stress granules and enable the synthesis of viral proteins using the host translation machinery.

  • Stress granules facilitate the establishment of an antiviral state by limiting viral protein accumulation and regulating signalling cascades that affect virus replication and immune responses.

  • Mechanisms have been described that enable the ongoing translation of messenger ribonucleoproteins (mRNPs) that encode antiviral factors such as interferon-stimulated genes (ISGs) despite the arrest of bulk translation.

  • Further elucidation of the role of stress granules in antiviral defence will probably depend on recent technical advances in translatome analysis and super-resolution microscopy, which have revolutionized our ability to study the composition and properties of stress granules.

Abstract

Efficient viral gene expression is threatened by cellular stress response programmes that rapidly reprioritize the translation machinery in response to varied environmental assaults, including virus infection. This results in inhibition of bulk synthesis of housekeeping proteins and causes the aggregation of messenger ribonucleoprotein complexes into cytoplasmic foci that are known as stress granules, which can entrap viral mRNAs. There is accumulating evidence for the antiviral nature of stress granules, which is supported by the discovery of many viral factors that interfere with stress granule formation and/or function. This Review focuses on recent advances in our understanding of the role of translation inhibition and stress granules in antiviral immune responses.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Translation arrest and stress granule formation.
Figure 2: Stress granule formation in response to viral pathogen-associated molecular patterns.
Figure 3: Translation arrest and viral replication.

Similar content being viewed by others

References

  1. Anderson, P. & Kedersha, N. RNA granules: post-transcriptional and epigenetic modulators of gene expression. Nat. Rev. Mol. Cell Biol. 10, 430–436 (2009).

    CAS  PubMed  Google Scholar 

  2. Anderson, P. & Kedersha, N. Stress granules: the Tao of RNA triage. Trends Biochem. Sci. 33, 141–150 (2008).

    CAS  PubMed  Google Scholar 

  3. Kedersha, N., Ivanov, P. & Anderson, P. Stress granules and cell signaling: more than just a passing phase? Trends Biochem. Sci. 38, 494–506 (2013).

    CAS  PubMed  Google Scholar 

  4. McInerney, G. M., Kedersha, N. L., Kaufman, R. J., Anderson, P. & Liljeström, P. Importance of eIF2α phosphorylation and stress granule assembly in alphavirus translation regulation. Mol. Biol. Cell 16, 3753–3763 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Onomoto, K. et al. Critical role of an antiviral stress granule containing RIG-I and PKR in viral detection and innate immunity. PLoS ONE 7, e43031 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Jackson, R. J., Hellen, C. U. T. & Pestova, T. V. The mechanism of eukaryotic translation initiation and principles of its regulation. Nat. Rev. Mol. Cell Biol. 11, 113–127 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Protter, D. S. W. & Parker, R. Principles and properties of stress granules. Trends Cell Biol. 26, 668–679 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. White, J. P. & Lloyd, R. E. Regulation of stress granules in virus systems. Trends Microbiol. 20, 175–183 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Poblete-Duran, N., Prades-Perez, Y., Vera-Otarola, J., Soto-Rifo, R. & Valiente-Echeverria, F. Who regulates whom? An overview of RNA granules and viral infections. Viruses 8, E180 (2016).

    PubMed  Google Scholar 

  10. Zoncu, R., Efeyan, A. & Sabatini, D. M. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell Biol. 12, 21–35 (2011).

    CAS  PubMed  Google Scholar 

  11. von der Haar, T., Gross, J. D., Wagner, G. & McCarthy, J. E. G. The mRNA cap-binding protein eIF4E in post-transcriptional gene expression. Nat. Struct. Mol. Biol. 11, 503–511 (2004).

    CAS  PubMed  Google Scholar 

  12. McEwen, E. et al. Heme-regulated inhibitor kinase-mediated phosphorylation of eukaryotic translation initiation factor 2 inhibits translation, induces stress granule formation, and mediates survival upon arsenite exposure. J. Biol. Chem. 280, 16925–16933 (2005).

    CAS  PubMed  Google Scholar 

  13. Lu, L., Han, A. & Chen, J. Translation initiation control by heme-regulated eukaryotic initiation factor 2α kinase in erythroid cells under cytoplasmic stresses. Mol. Cell. Biol. 21, 7971–7980 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Wek, S. A., Zhu, S. & Wek, R. C. The histidyl-tRNA synthetase-related sequence in the eIF-2α protein kinase GCN2 interacts with tRNA and is required for activation in response to starvation for different amino acids. Mol. Cell. Biol. 15, 4497–4506 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Deng, J. et al. Activation of GCN2 in UV-irradiated cells inhibits translation. Curr. Biol. 12, 1279–1286 (2002).

    CAS  PubMed  Google Scholar 

  16. García, M. A., Meurs, E. F. & Esteban, M. The dsRNA protein kinase PKR: virus and cell control. Biochimie 89, 799–811 (2007).

    PubMed  Google Scholar 

  17. Harding, H. P., Zhang, Y., Bertolotti, A., Zeng, H. & Ron, D. Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol. Cell 5, 897–904 (2000).

    CAS  PubMed  Google Scholar 

  18. Panniers, R. Translational control during heat shock. Biochimie 76, 737–747 (1994).

    CAS  PubMed  Google Scholar 

  19. Thomas, M. G., Loschi, M., Desbats, M. A. & Boccaccio, G. L. RNA granules: the good, the bad and the ugly. Cell. Signal. 23, 324–334 (2011).

    CAS  PubMed  Google Scholar 

  20. Vattem, K. M. & Wek, R. C. Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proc. Natl Acad. Sci. USA 101, 11269–11274 (2004).

    CAS  PubMed  Google Scholar 

  21. Novoa, I. et al. Stress-induced gene expression requires programmed recovery from translational repression. EMBO J. 22, 1180–1187 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Low, W.-K. et al. Inhibition of eukaryotic translation initiation by the marine natural product pateamine A. Mol. Cell 20, 709–722 (2005).

    CAS  PubMed  Google Scholar 

  23. Mazroui, R. et al. Inhibition of ribosome recruitment induces stress granule formation independently of eukaryotic initiation factor α phosphorylation. Mol. Biol. Cell 17, 4212–4219 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Hagner, P. R. et al. Ribosomal protein S6 is highly expressed in non-Hodgkin lymphoma and associates with mRNA containing a 5′ terminal oligopyrimidine tract. Oncogene 30, 1531–1541 (2011).

    CAS  PubMed  Google Scholar 

  25. Fujimura, K., Sasaki, A. T. & Anderson, P. Selenite targets eIF4E-binding protein-1 to inhibit translation initiation and induce the assembly of non-canonical stress granules. Nucleic Acids Res. 40, 8099–8110 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Emara, M. M. et al. Hydrogen peroxide induces stress granule formation independent of eIF2α phosphorylation. Biochem. Biophys. Res. Commun. 423, 763–769 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Ohn, T., Kedersha, N., Hickman, T., Tisdale, S. & Anderson, P. A functional RNAi screen links O-GlcNAc modification of ribosomal proteins to stress granule and processing body assembly. Nat. Cell Biol. 10, 1224–1231 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Kedersha, N. et al. Dynamic shuttling of TIA-1 accompanies the recruitment of mRNA to mammalian stress granules. J. Cell Biol. 151, 1257–1268 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Ivanov, P. A., Chudinova, E. M. & Nadezhdina, E. S. Disruption of microtubules inhibits cytoplasmic ribonucleoprotein stress granule formation. Exp. Cell Res. 290, 227–233 (2003).

    CAS  PubMed  Google Scholar 

  30. Loschi, M., Leishman, C. C., Berardone, N. & Boccaccio, G. L. Dynein and kinesin regulate stress-granule and P-body dynamics. J. Cell Sci. 122, 3973–3982 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Anderson, P. & Kedersha, N. Visibly stressed: the role of eIF2, TIA-1, and stress granules in protein translation. Cell Stress Chaperones 7, 213–221 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Kedersha, N. L., Gupta, M., Li, W., Miller, I. & Anderson, P. RNA-binding proteins TIA-1 and TIAR link the phosphorylation of eIF-2α to the assembly of mammalian stress granules. J. Cell Biol. 147, 1431–1441 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Tourrière, H. et al. The RasGAP-associated endoribonuclease G3BP assembles stress granules. J. Cell Biol. 160, 823–831 (2003).

    PubMed  PubMed Central  Google Scholar 

  34. Kedersha, N. & Anderson, P. Mammalian stress granules and processing bodies. Methods Enzymol. 431, 61–81 (2007). This paper provides excellent protocols for the induction and immunofluorescent detection of stress granules, as well as information about commercially available antibodies for common stress granule markers.

    CAS  PubMed  Google Scholar 

  35. Gilks, N. et al. Stress granule assembly is mediated by prion-like aggregation of TIA-1. Mol. Biol. Cell 15, 5383–5398 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Matsuki, H. et al. Both G3BP1 and G3BP2 contribute to stress granule formation. Genes Cells 18, 135–146 (2013).

    CAS  PubMed  Google Scholar 

  37. Kedersha, N. et al. Stress granules and processing bodies are dynamically linked sites of mRNP remodeling. J. Cell Biol. 169, 871–884 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Wheeler, J. Distinct stages in stress granule assembly and disassembly. eLife 5, e18413 (2016).

    PubMed  PubMed Central  Google Scholar 

  39. Lin, Y., Protter, D. S. W., Rosen, M. K. & Parker, R. Formation and maturation of phase-separated liquid droplets by RNA-binding proteins. Mol. Cell 60, 208–219 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Kwon, S., Zhang, Y. & Matthias, P. The deacetylase HDAC6 is a novel critical component of stress granules involved in the stress response. Genes Dev. 21, 3381–3394 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Leung, A. K. L. et al. Poly(ADP-ribose) regulates stress responses and microRNA activity in the cytoplasm. Mol. Cell 42, 489–499 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Tsai, W.-C. et al. Arginine demethylation of G3BP1 promotes stress granule assembly. J. Biol. Chem. 291, 22671–22685 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Jayabalan, A. K. et al. NEDDylation promotes stress granule assembly. Nat. Commun. 7, 12125 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Rojas, M., Arias, C. F. & López, S. Protein kinase R is responsible for the phosphorylation of eIF2α in rotavirus infection. J. Virol. 84, 10457–10466 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Willis, K. L., Langland, J. O. & Shisler, J. L. Viral double-stranded RNAs from vaccinia virus early or intermediate gene transcripts possess PKR activating function, resulting in NF-κB activation, when the K1 protein is absent or mutated. J. Biol. Chem. 286, 7765–7778 (2011).

    CAS  PubMed  Google Scholar 

  46. Heinicke, L. A. et al. RNA dimerization promotes PKR dimerization and activation. J. Mol. Biol. 390, 319–338 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Nallagatla, S. R. et al. 5′-triphosphate-dependent activation of PKR by RNAs with short stem–loops. Science 318, 1455–1458 (2007).

    CAS  PubMed  Google Scholar 

  48. Nallagatla, S. R., Toroney, R. & Bevilacqua, P. C. Regulation of innate immunity through RNA structure and the protein kinase PKR. Curr. Opin. Struct. Biol. 21, 119–127 (2011).

    CAS  PubMed  Google Scholar 

  49. Dauber, B. et al. Influenza B virus ribonucleoprotein is a potent activator of the antiviral kinase PKR. PLoS Pathog. 5, e1000473 (2009).

    PubMed  PubMed Central  Google Scholar 

  50. Berlanga, J. J. et al. Antiviral effect of the mammalian translation initiation factor 2α kinase GCN2 against RNA viruses. EMBO J. 25, 1730–1740 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Chan, S.-W. & Egan, P. A. Hepatitis C virus envelope proteins regulate CHOP via induction of the unfolded protein response. FASEB J. 19, 1510–1512 (2005).

    CAS  PubMed  Google Scholar 

  52. Cheng, G., Feng, Z. & He, B. Herpes simplex virus 1 infection activates the endoplasmic reticulum resident kinase PERK and mediates eIF-2 dephosphorylation by the 134.5 protein. J. Virol. 79, 1379–1388 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Mohr, I. & Sonenberg, N. Host translation at the nexus of infection and immunity. Cell Host Microbe 12, 470–483 (2012).

    CAS  PubMed  Google Scholar 

  54. Jan, E., Mohr, I. & Walsh, D. A. Cap-to-tail guide to mRNA translation strategies in virus-infected cells. Annu. Rev. Virol. 3, 283–307 (2016).

    CAS  PubMed  Google Scholar 

  55. Khaperskyy, D. A., Hatchette, T. F. & McCormick, C. Influenza A virus inhibits cytoplasmic stress granule formation. FASEB J. 26, 1629–1639 (2012).

    CAS  PubMed  Google Scholar 

  56. White, J. P., Cardenas, A. M., Marissen, W. E. & Lloyd, R. E. Inhibition of cytoplasmic mRNA stress granule formation by a viral proteinase. Cell Host Microbe 2, 295–305 (2007). This is the first study to describe direct interference with stress granule formation by proteolytic cleavage of G3BP1 and show the antiviral effect of stress granule formation.

    CAS  PubMed  Google Scholar 

  57. Ruggieri, A. et al. Dynamic oscillation of translation and stress granule formation mark the cellular response to virus infection. Cell Host Microbe 12, 71–85 (2012). This is the first study to describe the dynamic oscillation of translation arrest and recovery as a feature of intrinsic immune responses to virus infection.

    CAS  PubMed  Google Scholar 

  58. Khaperskyy, D. A. et al. Influenza A virus host shutoff disables antiviral stress-induced translation arrest. PLoS Pathog. 10, e1004217 (2014).

    PubMed  PubMed Central  Google Scholar 

  59. Borghese, F. & Michiels, T. The leader protein of cardioviruses inhibits stress granule assembly. J. Virol. 85, 9614–9622 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Finnen, R. L., Zhu, M., Li, J., Romo, D. & Banfield, B. W. Herpes simplex virus 2 virion host shutoff endoribonuclease activity is required to disrupt stress granule formation. J. Virol. 90, 7943–7955 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Reikine, S., Nguyen, J. B. & Modis, Y. Pattern recognition and signaling mechanisms of RIG-I and MDA5. Front. Immunol. 5, 342 (2014).

    PubMed  PubMed Central  Google Scholar 

  62. Zeng, W. et al. Reconstitution of the RIG-I pathway reveals a signaling role of unanchored polyubiquitin chains in innate immunity. Cell 141, 315–330 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Wu, B. & Hur, S. How RIG-I like receptors activate MAVS. Curr. Opin. Virol. 12, 91–98 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Vazquez, C. & Horner, S. M. MAVS coordination of antiviral innate immunity. J. Virol. 89, 6974–6977 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Clavarino, G. et al. Induction of GADD34 is necessary for dsRNA-dependent interferon-β production and participates in the control of Chikungunya virus infection. PLoS Pathog. 8, e1002708 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Reineke, L. C. et al. Stress granules regulate double-stranded RNA-dependent protein kinase activation through a complex containing G3BP1 and caprin1. mBio 6, e02486 (2015).

    PubMed  PubMed Central  Google Scholar 

  67. Langereis, M. A., Feng, Q. & van Kuppeveld, F. J. MDA5 localizes to stress granules, but this localization is not required for the induction of type I interferon. J. Virol. 87, 6314–6325 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Sánchez-Aparicio, M. T., Ayllón, J., Leo-Macias, A., Wolff, T. & García-Sastre, A. Subcellular localizations of RIG-I, TRIM25 and MAVS complexes. J. Virol. 91, e01155–16 (2017).

    PubMed  PubMed Central  Google Scholar 

  69. Kim, W. J., Back, S. H., Kim, V., Ryu, I. & Jang, S. K. Sequestration of TRAF2 into stress granules interrupts tumor necrosis factor signaling under stress conditions. Mol. Cell. Biol. 25, 2450–2462 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Yoo, J.-S. et al. DHX36 enhances RIG-I signaling by facilitating PKR-mediated antiviral stress granule formation. PLoS Pathog. 10, e1004012 (2014).

    PubMed  PubMed Central  Google Scholar 

  71. Kim, T. et al. Aspartate-glutamate-alanine-histidine box motif (DEAH)/RNA helicase A helicases sense microbial DNA in human plasmacytoid dendritic cells. Proc. Natl Acad. Sci. USA 107, 15181–15186 (2010).

    CAS  PubMed  Google Scholar 

  72. Zhang, Z. et al. DDX1, DDX21, and DHX36 helicases form a complex with the adaptor molecule TRIF to sense dsRNA in dendritic cells. Immunity 34, 866–878 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Gack, M. U. et al. TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature 446, 916–920 (2007).

    CAS  PubMed  Google Scholar 

  74. Reineke, L. C. & Lloyd, R. E. The stress granule protein G3BP1 recruits protein kinase R to promote multiple innate immune antiviral responses. J. Virol. 89, 2575–2589 (2015). This study shows the positive feedback loop of PKR activation through its recruitment to stress granules by G3BP1.

    PubMed  Google Scholar 

  75. Schulz, O. et al. Protein kinase R contributes to immunity against specific viruses by regulating interferon mRNA integrity. Cell Host Microbe 7, 354–361 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Taghavi, N. & Samuel, C. E. Protein kinase PKR catalytic activity is required for the PKR-dependent activation of mitogen-activated protein kinases and amplification of interferon β induction following virus infection. Virology 427, 208–216 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Killip, M. J., Smith, M., Jackson, D. & Randall, R. E. Activation of the interferon induction cascade by influenza A viruses requires viral RNA synthesis and nuclear export. J. Virol. 88, 3942–3952 (2014).

    PubMed  PubMed Central  Google Scholar 

  78. Kato, H. et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441, 101–105 (2006).

    CAS  PubMed  Google Scholar 

  79. Liu, S.-Y., Sanchez, D. J., Aliyari, R., Lu, S. & Cheng, G. Systematic identification of type I and type II interferon-induced antiviral factors. Proc. Natl Acad. Sci. USA 109, 4239–4244 (2012).

    CAS  PubMed  Google Scholar 

  80. Lekmine, F. et al. Activation of the p70 S6 kinase and phosphorylation of the 4E-BP1 repressor of mRNA translation by type I interferons. J. Biol. Chem. 278, 27772–27780 (2003).

    CAS  PubMed  Google Scholar 

  81. Kaur, S. et al. Regulatory effects of mammalian target of rapamycin-activated pathways in type I and II interferon signaling. J. Biol. Chem. 282, 1757–1768 (2007).

    CAS  PubMed  Google Scholar 

  82. Clavarino, G. et al. Protein phosphatase 1 subunit Ppp1r15a/GADD34 regulates cytokine production in polyinosinic:polycytidylic acid-stimulated dendritic cells. Proc. Natl Acad. Sci. USA 109, 3006–3011 (2012).

    CAS  PubMed  Google Scholar 

  83. Dalet, A. et al. Protein synthesis inhibition and GADD34 control IFN-β heterogeneous expression in response to dsRNA. EMBO J. 36, e201695000 (2017). This study thoroughly examines the translation arrest and antiviral cytokine synthesis that occur concomitantly in poly(I:C)-treated cells. It shows a novel mechanism of GADD34 induction via IRF3 activation and proposes a model for cycles of consecutive translation arrest and recovery.

    Google Scholar 

  84. Kojima, E. et al. The function of GADD34 is a recovery from a shutoff of protein synthesis induced by ER stress: elucidation by GADD34-deficient mice. FASEB J. 17, 1573–1575 (2003).

    CAS  PubMed  Google Scholar 

  85. Diamond, M. S. & Farzan, M. The broad-spectrum antiviral functions of IFIT and IFITM proteins. Nat. Rev. Immunol. 13, 46–57 (2012).

    PubMed  PubMed Central  Google Scholar 

  86. Silverman, R. H. Viral encounters with 2′,5′-oligoadenylate synthetase and RNase L during the interferon antiviral response. J. Virol. 81, 12720–12729 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Teijaro, J. R. Type I interferons in viral control and immune regulation. Curr. Opin. Virol. 16, 31–40 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. George, C. X., Ramaswami, G., Li, J. B. & Samuel, C. E. Editing of cellular self-RNAs by adenosine deaminase ADAR1 suppresses innate immune stress responses. J. Biol. Chem. 291, 6158–6168 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Kristiansen, H., Gad, H. H., Eskildsen-Larsen, S., Despres, P. & Hartmann, R. The oligoadenylate synthetase family: an ancient protein family with multiple antiviral activities. J. Interferon Cytokine Res. 31, 41–47 (2011).

    CAS  PubMed  Google Scholar 

  90. Zhu, J. et al. Antiviral activity of human OASL protein is mediated by enhancing signaling of the RIG-I RNA sensor. Immunity 40, 936–948 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Welsby, I. et al. PARP12, an interferon-stimulated gene involved in the control of protein translation and inflammation. J. Biol. Chem. 289, 26642–26657 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Lee, H. et al. Zinc-finger antiviral protein mediates retinoic acid inducible gene I-like receptor-independent antiviral response to murine leukemia virus. Proc. Natl Acad. Sci. USA 110, 12379–12384 (2013).

    CAS  PubMed  Google Scholar 

  93. Karlberg, T. et al. Structural basis for lack of ADP-ribosyltransferase activity in poly(ADP-ribose) polymerase-13/zinc finger antiviral protein. J. Biol. Chem. 290, 7336–7344 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Gagne, J.-P. et al. Proteome-wide identification of poly(ADP-ribose) binding proteins and poly(ADP-ribose)-associated protein complexes. Nucleic Acids Res. 36, 6959–6976 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Isabelle, M., Gagné, J.-P., Gallouzi, I.-E. & Poirier, G. G. Quantitative proteomics and dynamic imaging reveal that G3BP-mediated stress granule assembly is poly(ADP-ribose)-dependent following exposure to MNNG-induced DNA alkylation. J. Cell Sci. 125, 4555–4566 (2012).

    CAS  PubMed  Google Scholar 

  96. Thulasi Raman, S. N. et al. DDX3 interacts with influenza A virus NS1 and NP proteins and exerts antiviral function through regulation of stress granule formation. J. Virol. 90, 3661–3675 (2016).

    PubMed  PubMed Central  Google Scholar 

  97. Li, T. et al. NF90 is a novel influenza A virus NS1-interacting protein that antagonizes the inhibitory role of NS1 on PKR phosphorylation. FEBS Lett. 590, 2797–2810 (2016).

    CAS  PubMed  Google Scholar 

  98. Wen, X. et al. NF90 exerts antiviral activity through regulation of PKR phosphorylation and stress granules in infected cells. J. Immunol. 192, 3753–3764 (2014).

    CAS  PubMed  Google Scholar 

  99. Wang, P. et al. Nuclear factor 90 negatively regulates influenza virus replication by interacting with viral nucleoprotein. J. Virol. 83, 7850–7861 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Scholte, F. E. M. et al. Stress granule components G3BP1 and G3BP2 play a proviral role early in Chikungunya virus replication. J. Virol. 89, 4457–4469 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Nelson, E. V. et al. Ebola virus does not induce stress granule formation during infection and sequesters stress granule proteins within viral inclusions. J. Virol. 90, 7268–7284 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Simpson-Holley, M. et al. Formation of antiviral cytoplasmic granules during orthopoxvirus infection. J. Virol. 85, 1581–1593 (2011). This study describes the unique antiviral granules that form in vaccinia virus-infected cells; these granules share components of stress granules but differ in terms of their composition and properties.

    CAS  PubMed  Google Scholar 

  103. Albornoz, A., Carletti, T., Corazza, G. & Marcello, A. The stress granule component TIA-1 binds tick-borne encephalitis virus RNA and is recruited to perinuclear sites of viral replication to inhibit viral translation. J. Virol. 88, 6611–6622 (2014).

    PubMed  PubMed Central  Google Scholar 

  104. Garaigorta, U. & Chisari, F. V. Hepatitis C virus blocks interferon effector function by inducing protein kinase R phosphorylation. Cell Host Microbe 6, 513–522 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Lindquist, M. E., Lifland, A. W., Utley, T. J., Santangelo, P. J. & Crowe, J. E. Respiratory syncytial virus induces host RNA stress granules to facilitate viral replication. J. Virol. 84, 12274–12284 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Pelletier, J. & Sonenberg, N. Internal initiation of translation of eukaryotic mRNA directed by a sequence derived from poliovirus RNA. Nature 334, 320–325 (1988).

    CAS  PubMed  Google Scholar 

  107. Chaudhry, Y. et al. Caliciviruses differ in their functional requirements for eIF4F components. J. Biol. Chem. 281, 25315–25325 (2006).

    CAS  PubMed  Google Scholar 

  108. Ziehr, B., Lenarcic, E., Cecil, C. & Moorman, N. J. The eIF4AIII RNA helicase is a critical determinant of human cytomegalovirus replication. Virology 489, 194–201 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Biedenkopf, N. et al. The natural compound silvestrol is a potent inhibitor of Ebola virus replication. Antiviral Res. 137, 76–81 (2017).

    CAS  PubMed  Google Scholar 

  110. Le Sage, V., Cinti, A., Amorim, R. & Mouland, A. J. Adapting the stress response: viral subversion of the mTOR signaling pathway. Viruses 8, E152 (2016).

    PubMed  Google Scholar 

  111. Montaner, S. Akt/TSC/mTOR activation by the KSHV G protein-coupled receptor: emerging insights into the molecular oncogenesis and treatment of Kaposi's sarcoma. Cell Cycle 6, 438–443 (2007).

    CAS  PubMed  Google Scholar 

  112. Krams, S. M. & Martinez, O. M. Epstein–Barr virus, rapamycin, and host immune responses. Curr. Opin. Organ Transplant. 13, 563–568 (2008).

    PubMed  PubMed Central  Google Scholar 

  113. Thomson, A. W., Turnquist, H. R. & Raimondi, G. Immunoregulatory functions of mTOR inhibition. Nat. Rev. Immunol. 9, 324–337 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Keating, R. et al. The kinase mTOR modulates the antibody response to provide cross-protective immunity to lethal infection with influenza virus. Nat. Immunol. 14, 1266–1276 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Kedersha, N. et al. G3BP–caprin1–USP10 complexes mediate stress granule condensation and associate with 40S subunits. J. Cell Biol. 212, 845–860 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Holcik, M. & Sonenberg, N. Translational control in stress and apoptosis. Nat. Rev. Mol. Cell Biol. 6, 318–327 (2005).

    CAS  PubMed  Google Scholar 

  117. Parsyan, A. et al. mRNA helicases: the tacticians of translational control. Nat. Rev. Mol. Cell Biol. 12, 235–245 (2011).

    CAS  PubMed  Google Scholar 

  118. Rozelle, D. K., Filone, C. M., Kedersha, N. & Connor, J. H. Activation of stress response pathways promotes formation of antiviral granules and restricts virus replication. Mol. Cell. Biol. 34, 2003–2016 (2014).

    PubMed  PubMed Central  Google Scholar 

  119. Xia, J. et al. Dengue virus infection induces formation of G3BP1 granules in human lung epithelial cells. Arch. Virol. 160, 2991–2999 (2015).

    CAS  PubMed  Google Scholar 

  120. Patton, J. T. et al. The translation inhibitor silvestrol exhibits direct anti-tumor activity while preserving innate and adaptive immunity against EBV-driven lymphoproliferative disease. Oncotarget 6, 2693–2708 (2015). This study examines the effects of the translation inhibitor and stress granule inducer silvestrol on innate and adaptive immunity in vivo.

    PubMed  Google Scholar 

  121. Tian, Q., Taupin, J., Elledge, S., Robertson, M. & Anderson, P. Fas-activated serine/threonine kinase (FAST) phosphorylates TIA-1 during Fas-mediated apoptosis. J. Exp. Med. 182, 865–874 (1995).

    CAS  PubMed  Google Scholar 

  122. Förch, P. et al. The apoptosis-promoting factor TIA-1 is a regulator of alternative pre-mRNA splicing. Mol. Cell 6, 1089–1098 (2000).

    PubMed  Google Scholar 

  123. Fournier, M.-J. et al. Inactivation of the mTORC1–eukaryotic translation initiation factor 4E pathway alters stress granule formation. Mol. Cell. Biol. 33, 2285–2301 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Chernov, K. G. et al. Atomic force microscopy reveals binding of mRNA to microtubules mediated by two major mRNP proteins YB-1 and PABP. FEBS Lett. 582, 2875–2881 (2008).

    CAS  PubMed  Google Scholar 

  125. Arimoto, K., Fukuda, H., Imajoh-Ohmi, S., Saito, H. & Takekawa, M. Formation of stress granules inhibits apoptosis by suppressing stress-responsive MAPK pathways. Nat. Cell Biol. 10, 1324–1332 (2008).

    CAS  PubMed  Google Scholar 

  126. Gallois-Montbrun, S. et al. Antiviral protein APOBEC3G localizes to ribonucleoprotein complexes found in P bodies and stress granules. J. Virol. 81, 2165–2178 (2007).

    CAS  PubMed  Google Scholar 

  127. Brai, A. et al. Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents. Proc. Natl Acad. Sci. USA 113, 5388–5393 (2016).

    CAS  PubMed  Google Scholar 

  128. Nawaz, M. S. et al. Regulation of human endonuclease V activity and relocalization to cytoplasmic stress granules. J. Biol. Chem. 291, 21786–21801 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Parker, L. M., Fierro-Monti, I. & Mathews, M. B. Nuclear factor 90 is a substrate and regulator of the eukaryotic initiation factor 2 kinase double-stranded RNA-activated protein kinase. J. Biol. Chem. 276, 32522–32530 (2001).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants to C.M. from the Natural Sciences and Engineering Research Council of Canada (RGPIN-341940) and the Canadian Institutes of Health Research (MOP-136817 and PJT-148727). The authors thank members of the McCormick laboratory for providing feedback on the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Craig McCormick.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Eukaryotic translation initiation factor 4F complex

(eIF4F complex). A complex formed from the translation initiation factors eIF4E, eIF4G and eIF4A bound to the 5′ cap of mRNA.

eIF2–GDP

The form of eukaryotic translation initiation factor 2 (eIF2) that needs to exchange GDP for GTP to be able to form the eIF2–GTP–Met–tRNAMet ternary complex that is required for subsequent rounds of translation initiation.

eIF2–GTP–Met–tRNAMet ternary complex

A translation initiation-competent complex that brings methionine amino-acyl tRNA to the 48S pre-initiation complex.

48S pre-initiation complex

A complex that is formed from mRNA, the eukaryotic translation initiation factors eIF4F, polyadenylate-binding protein 1, eIF3, eIF1, eIF1A, eIF5 and eIF2, and the 40S small ribosomal subunit, and that is poised for the recognition of the initiation codon and for the recruitment of the large ribosomal subunit.

Initiation codon

The first AUG triplet that is recognized by the tRNAMet anticodon.

Stalled 48S mRNPs

48S pre-initiation complexes that are unable to recruit the large ribosomal subunit and initiate polypeptide synthesis.

Pateamine A

A small-molecule inhibitor of the helicase function of eukaryotic translation initiation factor 4A. It is a natural product derived from marine sponges of the Mycale genus.

Polysome

A structure formed from mRNA bound by multiple elongating ribosomes.

Low complexity and intrinsically disordered domains

Regions or domains of proteins that have reduced diversity in terms of their amino acid composition, which exist in a disordered state.

Liquid–liquid phase separation

The formation of droplets that concentrate macromolecules such as proteins and RNA within an aqueous solution. Macromolecules are held within phase-separated droplets by multiple weak interactions while retaining the ability to diffuse in and out of the droplets.

HIV transactivation-response region RNA hairpins

RNA elements within the HIV genome that are the binding sites for the HIV trans-activator protein Tat and that form multiple secondary structures.

Internal ribosome entry sites

(IRESs). RNA elements that fold into secondary structures that function as platforms for the internal recruitment of the translation initiation machinery.

BirA

A biotin ligase from Escherichia coli that biotinylates acetyl-CoA carboxylase subunits. A mutant form of this enzyme that has a relaxed specificity is used in proximity-dependent biotin identification (BioID) proteomics.

APEX

In the context of this Review, refers to an engineered ascorbate peroxidase that is used for proximity-dependent biotin labelling in proteomics methods.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

McCormick, C., Khaperskyy, D. Translation inhibition and stress granules in the antiviral immune response. Nat Rev Immunol 17, 647–660 (2017). https://doi.org/10.1038/nri.2017.63

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri.2017.63

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing