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:

The TORrid affairs of viruses: effects of mammalian DNA viruses on the PI3K–Akt–mTOR signalling pathway

Nature Reviews Microbiology volume 6, pages 266–275 (2008)Cite this article

Key Points

  • The successful replication of mammalian DNA viruses requires viral adaptation of the host cell to establish an environment that can accommodate the increased demands for nutrients, energy and macromolecular synthesis that accompany viral infection. Therefore, the DNA viruses must gain control of key cellular signalling pathways that affect broad aspects of cellular macromolecular synthesis, metabolism, growth and survival, such as the phosphatidylinositol 3′-kinase–Akt–mammalian target of rapamycin (PI3K–Akt–mTOR) pathway. However, a viral mechanism for activating this pathway is not enough; to maintain control of this pathway, viruses must also overcome the many controls that cells use to inhibit this pathway when cellular stress responses are activated during viral infection.

  • This Review discusses the normal activation and control of the PI3K–Akt–mTOR pathway, and why the activation and control of this pathway is important to mammalian DNA viruses.

  • The authors also outline how the PI3K–Akt–mTOR pathway can be inhibited by signalling that is induced by the stress that is imposed on the cell by the viral lytic infection, for example, by the depletion of nutrients, energy, amino acids or oxygen.

  • The range of mechanisms that mammalian DNA viruses use to activate the PI3K–Akt–mTOR pathway are discussed, as well as the multiple mechanisms that these viruses have evolved to circumvent the inhibitory stress signalling that would normally inhibit this pathway.

  • This Review ends with a discussion of remaining questions about the viral control of the PI3K–Akt–mTOR pathway and how the manipulation of the pathway, and its downstream effectors, may contribute to viral pathogenesis.

Abstract

The successful replication of mammalian DNA viruses requires that they gain control of key cellular signalling pathways that affect broad aspects of cellular macromolecular synthesis, metabolism, growth and survival. The phosphatidylinositol 3′-kinase–Akt–mammalian target of rapamycin (PI3K–Akt–mTOR) pathway is one such pathway. Mammalian DNA viruses have evolved various mechanisms to activate this pathway to obtain the benefits of Akt activation, including the maintenance of translation through the activation of mTOR. In addition, viruses must overcome the inhibition of this pathway that results from the activation of cellular stress responses during viral infection. This Review will discuss the range of mechanisms that mammalian DNA viruses use to activate this pathway, as well as the multiple mechanisms these viruses have evolved to circumvent inhibitory stress signalling.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Receptor-mediated activation of phosphatidylinositol 3′-kinase (PI3K) and activation of Akt.
Figure 2: PI3K–Akt–mTOR signalling.
Figure 3: Mechanisms by which mTORC1 activity controls cap-dependent translation.
Figure 4: Summary of the effects of mammalian DNA viruses on the components of the PI3K–Akt–mTOR pathway, the substrates of mTORC1 and the eIF4F complex.

Similar content being viewed by others

References

  1. Cooray, S. The pivotal role of phosphatidylinositol3-kinase-Akt signal transduction in virus survival. J. Gen. Virol. 85, 1065–1076 (2004). An overview of the importance of the control of Akt to most viruses.

    Article  CAS  PubMed  Google Scholar 

  2. Arsham, A. M., Howell, J. J. & Simon, M. C. A novel hypoxia-inducible factor-independent hypoxic response regulating mammalian target of rapamycin and its targets. J. Biol. Chem. 278, 29655–29660 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Kaufman, R. J. et al. The unfolded protein response in nutrient sensing and differentiation. Nature Rev. Mol. Cell Biol. 3, 411–421 (2002).

    Article  CAS  Google Scholar 

  4. Wek, R. C., Jiang, H. Y. & Anthony, T. G. Coping with stress: eIF2 kinases and translational control. Biochem. Soc. Trans. 34, 7–11 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Wouters, B. G. et al. Control of the hypoxic response through regulation of mRNA translation. Sem. Cell Dev. Biol. 16, 487–501 (2005).

    Article  CAS  Google Scholar 

  6. Holcik, M. & Sonenberg, N. Translational control in stress and apoptosis. Nature Rev. Mol. Cell Biol. 6, 318–327 (2005). Reviews the various ways that stress can affect translation.

    Article  CAS  Google Scholar 

  7. Bellacosa, A., Testa, J. R., Staal, S. P. & Tsichlis, P. N. A retroviral oncogene, akt, encoding a serine–threonine kinase containing an SH2-like region. Science 254, 274–277 (1991).

    Article  CAS  PubMed  Google Scholar 

  8. Datta, S. R., Brunet, A. & Greenberg, M. E. Cellular survival: a play in three Akts. Genes Dev. 13, 2905–2927 (1999). An older review that outlines the many functions of Akt.

    Article  CAS  PubMed  Google Scholar 

  9. Sarbassov, D. D., Guertin, D. A., Ali, S. M. & Sabatini, D. M. Phosphorylation and regulation of Akt/PKB by the rictor–mTOR complex. Science. 307, 1098–1101 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Plas, D. R. & Thompson, C. B. Akt-dependent transformation: there is more to growth than just surviving. Oncogene 24, 7435–7442 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Baker, S. J. PTEN enters the nuclear age. Cell 128, 25–28 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Cass, L. A. et al. Protein kinase A-dependent and -independent signaling pathways contribute to cyclic AMP-stimulated proliferation. Mol. Cell. Biol. 19, 5882–5891 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Summers, S. A., Garza, L. A., Zhou, H. & Birnbaum, M. J. Regulation of insulin-stimulated glucose transporter GLUT4 translocation and Akt kinase activity by ceramide. Mol. Cell. Biol. 18, 5457–5464 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hill, M. M. et al. A role for protein kinase Bβ/Akt2 in insulin-stimulated GLUT4 translocation in adipocytes. Mol. Cell. Biol. 19, 7771–7781 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ueki, K. et al. Potential role of protein kinase B in insulin-induced glucose transport, glycogen synthesis, and protein synthesis. J. Biol. Chem. 273, 5315–5322 (1998).

    Article  CAS  PubMed  Google Scholar 

  16. Jozwiak, J. Hamartin and tuberin: working together for tumour suppression. Int. J. Cancer. 118, 1–5 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Krymskaya, V. P. Tumour suppressors hamartin and tuberin: intracellular signalling. Cell. Signal. 15, 729–739 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Long, X., Lin, Y., Ortiz-Vega, S., Yonezawa, K. & Avruch, J. Rheb binds and regulates the mTOR kinase. Curr. Biol. 15, 702–713 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Long, X., Ortiz-Vega, S., Lin, Y. & Avruch, J. Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino acid sufficiency. J. Biol. Chem. 280, 23433–23436 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Astrinidis, A. & Henske, E. P. Tuberous sclerosis complex: linking growth and energy signaling pathways with human disease. Oncogene 24, 7475–7481 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Avruch, J. et al. Insulin and amino-acid regulation of mTOR signaling and kinase activity through the Rheb GTPase. Oncogene 25, 6361–6372 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Bai, X. et al. Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38. Science 318, 977–980 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Kim, D. H. et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163–175 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Sarbassov, D. D. et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14, 1296–1302 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Kim, D. H. et al. GβL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol. Cell 11, 895–904 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Jacinto, E. et al. SIN1/MIP1 maintains rictor–mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127, 125–137 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Yang, Q., Inoki, K., Ikenoue, T., Guan, K. L. & Iaccheri, L. Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes Dev. 20, 2820–2832 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Polak, P. & Hall, M. N. mTORC2 caught in a SINful Akt. Dev. Cell 11, 433–434 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Sarbassov, D. D., Ali, S. M. & Sabatini, D. M. Growing roles for the mTOR pathway. Curr. Opin. Cell Biol. 17, 596–603 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Reiling, J. H. & Sabatini, D. M. Stress and mTORture signaling. Oncogene 25, 6373–6383 (2006). An overview of the effects of stress on mTOR signalling and translation.

    Article  CAS  PubMed  Google Scholar 

  31. Mamane, Y., Petroulakis, E., LeBacquer, O. & Sonenberg, N. mTOR, translation initiation and cancer. Oncogene 25, 6416–6422 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Jacinto, E. et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nature Cell Biol. 6, 1122–1128 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Yang, Q., Inoki, K., Kim, E. & Guan, K. L. TSC1/TSC2 and Rheb have different effects on TORC1 and TORC2 activity. Proc. Natl Acad. Sci. USA 103, 6811–6816 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Brugarolas, J. et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 18, 2893–2904 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Arsham, A. M., Plas, D. R., Thompson, C. B. & Simon, M. C. PI3-K/Akt signaling is neither required for hypoxic stabilization of HIF-1 nor sufficient for HIF-1-dependent target gene transcription. J. Biol. Chem. 277, 15162–15170 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Cai, S. L. et al. Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning. J. Cell Biol. 173, 279–289 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. van den Beucken, T., Koritzinsky, M. & Wouters, B. G. Translational control of gene expression during hypoxia. Cancer Biol. Ther. 5, 749–755 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Ellisen, L. W. Growth control under stress: mTOR regulation through the REDD1–TSC pathway. Cell Cycle 4, 1500–1502 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Schwarzer, R. et al. REDD1 integrates hypoxia-mediated survival signaling downstream of phosphatidylinositol 3-kinase. Oncogene 24, 1138–1149 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Corradetti, M. N., Inoki, K., Bardeesy, N., DePinho, R. A. & Guan, K. L. Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz–Jeghers syndrome. Genes Dev. 18, 1533–1538 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Shaw, R. J. et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6, 91–99 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Kimble, S. R. Interaction between the AMP-activated protein kinase and mTOR signaling pathways. Med. Sci. Sports Exerc. 38, 1958–1964 (2006).

    Article  CAS  Google Scholar 

  43. Luo, Z., Saha, A. K., Xiang, X. & Ruderman, N. B. AMPK, the metabolic syndrome and cancer. Trends Pharmacol. Sci. 26, 69–76 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Hardie, D. G. AMP-activated protein kinase as a drug target. Annu. Rev. Pharmacol. Toxicol. 47, 185–210 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Chami, M., Oules, B. & Paterlini-Brechot, P. Cytobiological consequences of calcium-signaling alterations induced by human viral proteins. Biochim. Biophys. Acta 1763, 1344–1362 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Avruch, J. et al. Insulin and amino-acid regulation of mTOR signaling and kinase activity through the Rheb GTPase. Oncogene 25, 6361–6372 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Vezina, C., Kudelski, A. & Sehgal, S. N. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J. Antibiot. 28, 721–726 (1975).

    Article  CAS  Google Scholar 

  48. Sarbassov, D. D. et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 22, 159–168 (2006).

    Article  CAS  PubMed  Google Scholar 

  49. Zeng, Z. et al. Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood 109, 3509–3512 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Gottlieb, K. A. & Villarreal, L. P. Natural biology of polyomavirus middle T antigen. Microbiol. Mol. Biol. Rev. 65, 288–318 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ichaso, N. & Dilworth, S. M. Cell transformation by the middle T-antigen of polyoma virus. Oncogene 20, 7908–7916 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. Utermark, T., Schaffhausen, B. S., Roberts, T. M. & Zhao, J. J. The p110α isoform of phosphatidylinositol 3-kinase is essential for polyomavirus middle T antigen-mediated transformation. J. Virol. 81, 7069–7076 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Summers, S. A., Lipfert, L. & Birnbaum, M. J. Polyoma middle T antigen activates the Ser/Thr kinase Akt in a PI3-kinase-dependent manner. Biochem. Biophys. Res. Commun. 246, 76–81 (1998).

    Article  CAS  PubMed  Google Scholar 

  54. Kaplan, D. R. et al. Common elements in growth factor stimulation and oncogenic transformation: 85 kd phosphoprotein and phosphatidylinositol kinase activity. Cell 50, 1021–1029 (1987).

    Article  CAS  PubMed  Google Scholar 

  55. Kaplan, D. R. et al. Phosphatidylinositol metabolism and polyoma-mediated transformation. Proc. Natl Acad. Sci. USA 83, 3624–3628 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Whitman, M., Kaplan, D. R., Schaffhausen, B., Cantley, L. & Roberts, T. M. Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation. Nature 315, 239–242 (1985).

    Article  CAS  PubMed  Google Scholar 

  57. Andrabi, S., Gjoerup, O. V., Kean, J. A., Roberts, T. M. & Schaffhausen, B. Protein phosphatase 2A regulates life and death decisions via Akt in a context-dependent manner. Proc. Natl Acad. Sci. USA 104, 19011–19016 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Simmons, D. T. SV40 large T antigen functions in DNA replication and transformation. Adv. Virus Res. 55, 75–134 (2000). A comprehensive review of SV40 large-T-antigen functions.

    Article  CAS  PubMed  Google Scholar 

  59. DeAngelis, T., Chen, J., Wu, A., Prisco, M. & Baserga, R. Transformation by the simian virus 40 T antigen is regulated by IGF-I receptor and IRS-1 signaling. Oncogene 25, 32–42 (2006).

    Article  CAS  PubMed  Google Scholar 

  60. Rundell, K. & Parakati, R. The role of the SV40 ST antigen in cell growth promotion and transformation. Semin. Cancer Biol. 11, 5–13 (2001). A review of the function of the SV40 small-t antigen.

    Article  CAS  PubMed  Google Scholar 

  61. Yang, S. I. et al. Control of protein phosphatase 2A by simian virus 40 small-t antigen. Mol. Cell. Biol. 11, 1988–1995 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Yang, C. S. et al. Simian virus 40 small t antigen mediates conformation-dependent transfer of protein phosphatase 2A onto the androgen receptor. Mol. Cell. Biol. 25, 1298–1308 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Yu, Y., Kudchodkar, S. B. & Alwine, J. C. Effects of simian virus 40 large and small tumor antigens on mammalian target of rapamycin (mTOR) signaling: small tumor antigen mediates hypophosphorylation of eIF4E-binding protein 1 late in infection. J. Virol. 79, 6882–6889 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Yu, Y. & Alwine, J. C. Human cytomegalovirus major immediate-early proteins and simian virus 40 large T antigen can inhibit apoptosis through activation of the phosphatidylinositide 3′-OH kinase pathway and cellular kinase Akt. J. Virol. 76, 3731–3738 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Yuan, H., Veldman, T., Rundell, K. & Schlegel, R. Simian virus 40 small tumor antigen activates AKT and telomerase and induces anchorage-independent growth of human epithelial cells. J. Virol. 76, 10685–10691 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Backer, J. M. et al. Phosphatidylinositol 3′-kinase is activated by association with IRS-1 during insulin stimulation. EMBO J. 11, 3469–3479 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lange-Mutschler, J., Deppert, W., Hanke, K. & Hennin, R. Detection of simian virus 40 T-antigen-related antigens by a 125I-protein A-binding assay and by immunofluorescence microscopy on the surface of SV40 transformed monolayer cells. J. Gen. Virol. 52, 301–312 (1981).

    Article  CAS  PubMed  Google Scholar 

  68. Lange-Mutschler, J. & Henning, R. A subclass of simian virus 40 T antigen with a high cell surface binding affinity. Virology 127, 333–344 (1983).

    Article  CAS  PubMed  Google Scholar 

  69. Yu, Y. & Alwine, J. C. 19S late mRNAs of simian virus 40 have an internal ribosome entry site upstream of the virion structural protein 3 coding sequence. J. Virol. 80, 6553–6558 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Mirzamani, N., Salehian, P., Farhadi, M. & Tehran, E. A. Detection of EBV and HPV in nasopharyngeal carcinoma by in situ hybridization. Exp. Mol. Pathol. 81, 231–234 (2006).

    Article  CAS  PubMed  Google Scholar 

  71. Schiffman, M., Castle, P. E., Jeronimo, J., Rodriguez, A. C. & Wacholder, S. Human papillomavirus and cervical cancer. Lancet 370, 890–907 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Pim, D., Massimi, P., Dilworth, S. M. & Banks, L. Activation of the protein kinase B pathway by the HPV-16 E7 oncoprotein occurs through a mechanism involving interaction with PP2A. Oncogene 24, 7830–7838 (2005).

    Article  CAS  PubMed  Google Scholar 

  73. Menges, C. W., Baglia, L. A., Lapoint, R. & McCance, D. J. Human papillomavirus type 16 E7 up-regulates AKT activity through the retinoblastoma protein. Cancer Res. 66, 5555–5559 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Oh, K. J., Kalinina, A., Park, N. H. & Bagchi, S. Deregulation of eIF4E: 4E-BP1 in differentiated human papillomavirus-containing cells leads to high levels of expression of the E7 oncoprotein. J. Virol. 80, 7079–7088 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Kim, S. H. et al. Human papillomavirus 16 E5 up-regulates the expression of vascular endothelial growth factor through the activation of epidermal growth factor receptor, MEK/ ERK1,2 and PI3K/Akt. Cell. Mol. Life Sci. 63, 930–938 (2006).

    Article  CAS  PubMed  Google Scholar 

  76. Lu, Z. et al. Human papillomavirus 16 E6 oncoprotein interferences with insulin signaling pathway by binding to tuberin. J. Biol. Chem. 279, 35664–35670 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. O'Shea, C. C., Choi, S., McCormick, F. & Stokoe, D. Adenovirus overrides cellular checkpoints for protein translation. Cell Cycle 4, 883–888 (2005). A thorough study of adenovirus effects on several cell-signalling pathways.

    Article  CAS  PubMed  Google Scholar 

  78. Helt, A. M. & Galloway, D. A. Mechanims by which DNA tumor virus oncoproteins target the Rb family of pocket proteins. Carcinogenesis 24, 159–169 (2003).

    Article  CAS  PubMed  Google Scholar 

  79. Querido, E. et al. Degradation of p53 by adenovirus E4orf6 and E1B55K proteins occurs via a novel mechanism involving a Cullin-containing complex. Genes Dev. 15, 3104–3117 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Querido, E. et al. Regulation of p53 levels by the E1B 55-kilodalton protein and E4orf6 in adenovirus-infected cells. J. Virol. 71, 3788–3798 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. O'Shea, C. et al. Adenoviral proteins mimic nutrient/growth signals to activate the mTOR pathway for viral replication. EMBO J. 24, 1211–1221 (2005). Studies of the effects of adenoviruses on mTOR.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Gingras, A. C. & Sonenburg, N. Adenovirus infection inactivates the translational inhibitors 4E-BP1 and 4E-PB2. Virology 237, 182–186 (1997).

    Article  CAS  PubMed  Google Scholar 

  83. de Groot, R. P. et al. Induction of the mitogen-activated p70 S6 kinase by adenovirus E1A. Oncogene 10, 543–548 (1995).

    CAS  PubMed  Google Scholar 

  84. Boyer, J. & Ketner, G. Manipulation of early region 4. Methods Mol. Med. 130, 1–17 (2007).

    CAS  PubMed  Google Scholar 

  85. Frese, K. K. et al. Selective PDZ protein-dependent stimulation of phosphatidylinositol 3-kinase by the adenovirus E4-ORF1 oncoprotein. Oncogene 22, 710–721 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Kudchodkar, S., Yu, Y., Maguire, T. & Alwine, J. C. Human cytomegalovirus infection induces rapamycin insensitive phosphorylation of downstream effectors of mTOR kinase. J. Virol. 78, 11030–11039 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kudchodkar, S. B., Del Prete, G. Q., Maguire, T. G. & Alwine, J. C. AMPK-mediated inhibition of mTOR kinase is circumvented during immediate-early times of human cytomegalovirus infection. J. Virol. 81, 3649–3651 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Kudchodkar, S. B., Yu, Y., Maguire, T. G. & Alwine, J. C. Human cytomegalovirus infection alters the substrate specificities and rapamycin sensitivities of raptor- and rictor-containing complexes. Proc. Natl Acad. Sci. USA 103, 14182–14187 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Isler, J. A., Skalet, A. H. & Alwine, J. C. Human cytomegalovirus infection activates and regulates the unfolded protein response. J. Virol. 79, 6890–6899 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Isler, J. A., Maguire, T. G. & Alwine, J. C. Production of infectious HCMV virions is inhibited by drugs that disrupt calcium homeostasis in the endoplasmic reticulum. J. Virol. 79, 15338–15397 (2005).

    Google Scholar 

  91. Alwine, J. C. in Current Topics in Microbiology and Immunology Vol. 325 (eds Shenk, T. E. & Stinski, M. F.) 263–279 (Springer, New York, 2008). A complete overview of the effects of lytic HCMV infection on the PI3K–Akt–mTOR pathway.

    Google Scholar 

  92. Hakki, M. & Geballe, A. P. Double-stranded RNA binding by human cytomegalovirus pTRS1. J. Virol. 79, 7311–7318 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Walsh, D., Perez, C., Notary, J. & Mohr, I. Regulation of the translation initiation factor eIF4F by multiple mechanisms in human cytomegalovirus-infected cells. J. Virol. 79, 8057–8064 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Buchkovich, N. J. et al. Human cytomegalovirus specifically controls the levels of the endoplasmic reticulum chaperone BiP/GRP78, which is required for virion assembly. J. Virol. 82, 31–39 (2008).

    Article  CAS  PubMed  Google Scholar 

  95. Johnson, R. A., Wang, X., Ma, X. L., Huong, S. M. & Huang, E. S. Human cytomegalovirus up-regulates the phosphatidylinositol 3-kinase (PI3-K) pathway: inhibition of PI3-K activity inhibits viral replication and virus-induced signaling. J. Virol. 75, 6022–6032 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Shen, Y. H. et al. Human cytomegalovirus inhibits Akt-mediated eNOS activation through upregulating PTEN (phosphatase and tensin homolog deleted on chromosome 10). Cardiovasc. Res. 69, 502–511 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Smith, C. C. The herpes simplex virus type 2 protein ICP10PK: a master of versatility. Front. Biosci. 10, 2820–2831 (2005).

    Article  CAS  PubMed  Google Scholar 

  98. Langelier, Y. et al. The R1 subunit of herpes simplex virus ribonucleotide reductase is a good substrate for host cell protein kinases but is not itself a protein kinase. J. Biol. Chem. 273, 1435–1443 (1998).

    Article  CAS  PubMed  Google Scholar 

  99. Conner, J. The unique N terminus of herpes simplex virus type 1 ribonucleotide reductase large subunit is phosphorylated by casein kinase 2, which may have a homologue in Escherichia coli. J. Gen. Virol. 80, 1471–1476 (1999).

    Article  CAS  PubMed  Google Scholar 

  100. Benetti, L. & Roizman, B. Protein kinase B/Akt is present in activated form throughout the entire replicative cycle of ΔUS3 mutant virus but only at early times after infection with wild-type herpes simplex virus 1. J. Virol. 80, 3341–3348 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Walsh, D. & Mohr, I. Phosphorylation of eIF4E by Mnk-1 enhances HSV-1 translation and replication in quiescent cells. Genes Dev. 18, 660–672 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Walsh, D. & Mohr, I. Assembly of an active translation initiation factor complex by a viral protein. Genes Dev. 20, 461–472 (2006). Together with Reference 101, examined the ways that herpesviruses can activate cap-dependent translation at points downstream of mTOR.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Rahaus, M., Desloges, N. & Wolff, M. H. Varicella-zoster virus requires a functional PI3K/Akt/GSK-3 signaling cascade for efficient replication. Cell. Signal. 19, 312–318 (2007).

    Article  CAS  PubMed  Google Scholar 

  104. Moody, C. A. et al. Modulation of the cell growth regulator mTOR by Epstein–Barr virus-encoded LMP2A. J. Virol. 79, 5499–5506 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Scholle, F., Bendt, K. M. & Raab-Traub, N. Epstein–Barr virus LMP2A transforms epithelial cells, inhibits cell differentiation, and activates Akt. J. Virol. 74, 10681–10689 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Swart, R., Ruf, I. K., Sample, J. & Longnecker, R. Latent membrane protein 2A-mediated effects on the phosphatidylinositol 3-kinase/Akt pathway. J. Virol. 74, 10838–10845 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Sodhi, A. et al. The TSC2/mTOR pathway drives endothelial cell transformation induced by the Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor. Cancer Cell 10, 133–143 (2006).

    Article  CAS  PubMed  Google Scholar 

  108. Moss, B. in Field's Virology (eds Knipe, D. M. et al.) 2849–2883 (Lippincott Williams & Wilkins, Philadelphia, 2007).

    Google Scholar 

  109. Condit, R. C., Moussatche, N. & Traktman, P. In a nutshell: structure and assembly of the vaccinia virion. Adv. Virus Res. 66, 31–124 (2006).

    Article  CAS  PubMed  Google Scholar 

  110. Venkatesan, S., Gershowitz, A. & Moss, B. Modification of the 5′ end of mRNA: association of RNA triphosphatase with the RNA guanylyltransferase-RNA (guanine-7) methyltransferase complex from vaccinia virus. J. Biol. Chem. 255, 903–908 (1980).

    CAS  PubMed  Google Scholar 

  111. Walsh, D. et al. eIF4F architectural alterations accompany cellular translation initiation factor redistribution in poxvirus-infected cells. Mol. Cell. Biol. 4 Feb 2008 (doi:10.1128/MCB.01631-07).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Kerr, P. & McFadden, G. Immune responses to myxoma virus. Viral Immunol. 15, 229–246 (2002).

    Article  CAS  PubMed  Google Scholar 

  113. Fenner, F. Adventures with poxviruses of vertebrates. FEMS Microbiol. Rev. 24, 123–133 (2000).

    Article  CAS  PubMed  Google Scholar 

  114. Jackson, E. W., Dorn, C. R., Saito, J. K. & McKercher, D. G. Absence of serological evidence of myxoma virus infection in humans exposed during an outbreak of myxomatosis. Nature 211, 313–314 (1966).

    Article  CAS  PubMed  Google Scholar 

  115. McFadden, G. Poxvirus tropism. Nature Rev. Microbiol. 3, 201–213 (2005).

    Article  CAS  Google Scholar 

  116. Sypula, J., Wang, F., Ma, Y., Bell, J. C. & McFadden, G. Myxoma virus tropism in human tumor cells. Gene Ther. Mol. Biol. 8, 108–114 (2004).

    Google Scholar 

  117. Wang, G. et al. Infection of human cancer cells with myxoma virus requires Akt activation via interaction with a viral ankyrin-repeat host range factor. Proc. Natl Acad. Sci. USA 103, 4640–4645 (2006). Together with Reference 116, investigated the growth of MV in human tumour cells and the requirement for the activation of Akt.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Schneider, R. J. & Mohr, I. Translation initiation and viral tricks. Trends Biochem. Sci. 28, 130–136 (2003).

    Article  CAS  PubMed  Google Scholar 

  119. Ryabova, L. A., Pooggin, M. M. & Hohn, T. Viral strategies of translation initiation: ribosomal shunt and reinitiation. Prog. Nucleic Acid Res. Mol. Biol. 72, 1–39 (2002). Together with Reference 118, discusses the intriguing translational mechanisms that are exploited by viruses

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Hellen, C. U. T. & Sarnow, P. Internal ribosome entry sites in eukaryotic mRNA molecules. Genes Dev. 15, 1593–1612 (2001).

    Article  CAS  PubMed  Google Scholar 

  121. Flint, S. J., Enquist, L. W., Krug, R. M., Racaniello, V. R. & Skalka, A. M. (eds) Principles of Virology (American Society for Microbiology, Washington D.C., 2004).

    Google Scholar 

  122. Knipe, D. M. et al. (eds) Field's Virology (Lippincott Williams & Wilkins, Philadelphia, 2006). Together with Reference 121, provides a wealth of information on viral replication and all things virological.

    Google Scholar 

Download references

Acknowledgements

The authors thank S. Adams, A. Diehl, C. Simon, B. Keith, C. Thompson and T. Shenk for many discussions and help in the preparation of this manuscript. J.C.A. is funded by Public Health Services grants R01 CA28379-27 and R01 GM45773-16 from the National Institutes of Health and the Abramson Family Cancer Research Institute.

Author information

Author notes

  1. Nicholas J. Buchkovich, Yongjun Yu and Carisa A. Zampieri: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cancer Biology and Abramson Family Cancer Research Institute, University of Pennsylvania, 314 Biomedical Research Building, 421 Curie Blvd, Philadelphia, 19104-6142, Pennsylvania, USA

    Nicholas J. Buchkovich, Yongjun Yu, Carisa A. Zampieri & James C. Alwine

Authors
  1. Nicholas J. Buchkovich
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yongjun Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carisa A. Zampieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. James C. Alwine
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James C. Alwine.

Related links

Related links

DATABASES

Entrez Genome

EBV

HHV-7

HSV1

HSV2

KSHV

MV

Py virus

SV40

VV

Entrez Protein

ICP0

ICP10

M-T5

PyLT

PyMT

PyST

SVLT

FURTHER INFORMATION

James C. Alwine's homepage

Rights and permissions

Reprints and permissions

About this article

Cite this article

Buchkovich, N., Yu, Y., Zampieri, C. et al. The TORrid affairs of viruses: effects of mammalian DNA viruses on the PI3K–Akt–mTOR signalling pathway. Nat Rev Microbiol 6, 266–275 (2008). https://doi.org/10.1038/nrmicro1855

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro1855

This article is cited by

Search

Advanced 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