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Modulation of Host Cell Stress Responses by Human Cytomegalovirus

  • J. C. Alwine
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 325)

Human cytomegalovirus (HCMV) induces cellular stress responses during infection due to nutrient depletion, energy depletion, hypoxia and synthetic stress, e.g., endoplasmic reticulum (ER) stress. Cellular stress responses initiate processes that allow the cell to survive the stress; some of these may be beneficial to HCMV replication while others are not. Several studies show that HCMV manipulates stress response signaling in order to maintain beneficial effects while inhibiting detrimental effects. The inhibition of translation is the most common effect of stress responses that would be detrimental to HCMV infection. This chapter will focus on the mechanisms by which cap-dependent translation is maintained during HCMV infection through alterations of the phosphatidylinositol-3' kinase (PI3K)-Akt-tuberous sclerosis complex (TSC)-mammalian target of rapamycin (mTOR) signaling pathway. The emerging picture is that HCMV affects this pathway in multiple ways, thus ensuring that cap-dependent translation is maintained despite the induction of stress responses that would normally inhibit it. Such dramatic alterations of this pathway lead to questions of what other beneficial effects the virus might gain from these changes and how these changes may contribute to HCMV pathogenesis.

Keywords

Tuberous Sclerosis Complex Human Cytomegalovirus HCMV Infection Cellular Stress Response mTOR Kinase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Arsham AM, Plas DR, Thompson CB, Simon MC (2002) 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.PubMedCrossRefGoogle Scholar
  2. Arsham AM, Howell JJ, Simon MC (2003) A novel hypoxia-inducible factor-independent hypoxic response regulating mammalian target of rapamycin and its targets. J Biol Chem 278:29655–29660.PubMedCrossRefGoogle Scholar
  3. Astrinidis A, Henske EP (2005) Tuberous sclerosis complex: linking growth and energy signaling pathways with human disease. Oncogene 24:7475–7481.PubMedCrossRefGoogle Scholar
  4. Avruch J, Hara K, Lin Y, Liu M, Long X, Ortiz-Vega S, Yonezawa K (2006) Insulin and amino-acid regulation of mTOR signaling and kinase activity through the Rheb GTPase. Oncogene 25:6361–6372.PubMedCrossRefGoogle Scholar
  5. Baker SJ (2007) PTEN enters the nuclear age. Cell 128:25–28.PubMedCrossRefGoogle Scholar
  6. Banaszynski LA, Liu CW, Wandless TJ (2005) Characterization of the FKBP-rapamycin-FRB ternary complex. J Am Chem Soc 127:4715–4721.PubMedCrossRefGoogle Scholar
  7. Bellacosa A, Testa JR, Staal SP, Tsichlis PN (1991) A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-like region. Science 254:274–277.PubMedCrossRefGoogle Scholar
  8. Bjornsti MA, Houghton PJ (2004) The TOR pathway: a target for cancer therapy. Nat Rev Cancer 4:335–348.PubMedCrossRefGoogle Scholar
  9. Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT, Lane WS, Schreiber SL (1994) A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369:756–758.PubMedCrossRefGoogle Scholar
  10. Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG Jr (2004) Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 18:2893–2904.PubMedCrossRefGoogle Scholar
  11. Cai SL, Tee AR, Short JD, Bergeron JM, Kim J, Shen J, Guo R, Johnson CL, Kiguchi K, Walker CL (2006) Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning. J Cell Biol 173:279–289.PubMedCrossRefGoogle Scholar
  12. Cass LA, Summers SA, Prendergast GV, Backer JM, Birnbaum MJ, Meinkoth JL (1999) Protein kinase A-dependent and -independent signaling pathways contribute to cyclic AMP-stimulated proliferation. Mol Cell Biol 19:5882–5891.PubMedGoogle Scholar
  13. Chen J, Zheng XF, Brown EJ, Schreiber SL (1995) Identification of an 11-kDa FKBP12-rapamycin-binding domain within the 289-kDa FKBP12-rapamycin-associated protein and characterization of a critical serine residue. Proc Natl Acad Sci U S A 92:4947–4951.PubMedCrossRefGoogle Scholar
  14. Child SJ, Hakki M, De Niro KL, Geballe AP (2004) Evasion of cellular antiviral responses by human cytomegalovirus TRS1 and IRS1. J Virol 78:197–205.PubMedCrossRefGoogle Scholar
  15. Corradetti MN, Inoki K, Bardeesy N, DePinho RA, Guan KL (2004) 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.PubMedCrossRefGoogle Scholar
  16. Datta SR, Brunet A, Greenberg ME (1999) Cellular survival: a play in three Akts. Genes Dev 13:2905–2927.PubMedCrossRefGoogle Scholar
  17. Hakki M, Geballe AP (2005) Double-stranded RNA binding by human cytomegalovirus pTRS1. J Virol 79:7311–7318.PubMedCrossRefGoogle Scholar
  18. Hakki M, Marshall EE, De Niro KL, Geballe AP (2006) Binding and nuclear relocalization of protein kinase R by human cytomegalovirus TRS1. J Virol 80:11817–11826.PubMedCrossRefGoogle Scholar
  19. Halford WP, Kemp CD, Isler JA, Davido DJ, Schaffer PA (2001) ICP0, ICP4, or VP16 expressed from adenovirus vectors induces reactivation of latent herpes simplex virus type 1 in primary cultures of latently infected trigeminal ganglion cells. J Virol 75:6143–6153.PubMedCrossRefGoogle Scholar
  20. Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, Tokunaga C, Avruch J, Yonezawa K (2002) Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110:177–189.PubMedCrossRefGoogle Scholar
  21. Hardie DG (2007) AMP-activated protein kinase as a drug target. Annu Rev Pharmacol Toxicol 47:185–210.PubMedCrossRefGoogle Scholar
  22. Hill MM, Clark SF, Tucker DF, Birnbaum MJ, James DE, Macaulay SL (1999) A role for protein kinase Bbeta/Akt2 in insulin-stimulated GLUT4 translocation in adipocytes. Mol Cell Biol 19:7771–7781.PubMedGoogle Scholar
  23. Holcik M, Sonenberg N (2005) Translational control in stress and apoptosis. Nat Rev Mol Cell Biol 6:318–327.PubMedCrossRefGoogle Scholar
  24. Isaacson MK, Feire AL, Compton T (2007) The epidermal growth factor receptor is not required for human cytomegalovirus entry or signaling. J Virol 81:6241–6247.PubMedCrossRefGoogle Scholar
  25. Isler JA, Maguire TG, Alwine JC (2005a) Production of infectious HCMV virions is inhibited by drugs that disrupt calcium homeostasis in the endoplasmic reticulum. J Virol 79:15338–15397.Google Scholar
  26. Isler JA, Skalet AH, Alwine JC (2005b) Human cytomegalovirus infection activates and regulates the unfolded protein response. J Virol 79:6890–6899.PubMedCrossRefGoogle Scholar
  27. Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, Hall MN (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6:1122–1128.PubMedCrossRefGoogle Scholar
  28. Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY, Huang Q, Qin J, Su B (2006) SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127:125–137.PubMedCrossRefGoogle Scholar
  29. Johnson RA, Wang X, Ma XL, Huong SM, Huang ES (2001) 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.PubMedCrossRefGoogle Scholar
  30. Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y, Birnbaum MJ, Thompson CB (2005) AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 18:283–293.PubMedCrossRefGoogle Scholar
  31. Kaufman RJ, Scheuner D, Schroder M, Shen X, Lee K, Liu CY, Arnold SM (2002) The unfolded protein response in nutrient sensing and differentiation. Nature Rev Mol Cell Biol 3:411–421.CrossRefGoogle Scholar
  32. Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110:163–175.PubMedCrossRefGoogle Scholar
  33. Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, Tempst P, Sabatini DM (2003) GβL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 11:895–904.PubMedCrossRefGoogle Scholar
  34. Kimble SR (2006) Interaction between the AMP-activated protein kinase and mTOR signaling pathways. Med Sci Sports Exercise 38:1958–1964.CrossRefGoogle Scholar
  35. Knudson AG (1988) The genetics of childhood cancer. Bull Cancer 73:135–138.Google Scholar
  36. Kudchodkar SB, Yu Y, Maguire T, Alwine JC (2004) Human cytomegalovirus infection induces rapamycin insensitive phosphorylation of downstream effectors of mTOR kinase. J Virol 78:11030–11039.PubMedCrossRefGoogle Scholar
  37. Kudchodkar SB, Yu Y, Maguire TG, Alwine JC (2006) Human cytomegalovirus infection alters the substrate specificities and rapamycin sensitivities of raptor- and rictor-containing complexes. Proc Natl Acad Sci U S A 103:14182–14187.PubMedCrossRefGoogle Scholar
  38. Kudchodkar SB, Del Prete GQ, Maguire TG, Alwine JC (2007) AMPK-mediated inhibition of mTOR kinase is circumvented during immediate-early times of human cytomegalovirus infection. J Virol 81:3649–3651.PubMedCrossRefGoogle Scholar
  39. Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J (2005a) Rheb binds and regulates the mTOR kinase. Curr Biol 15:702–713.PubMedCrossRefGoogle Scholar
  40. Long X, Ortiz-Vega S, Lin Y, Avruch J (2005b) Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino acid sufficiency. J Biol Chem 280:23433–23436.PubMedCrossRefGoogle Scholar
  41. Luo Z, Saha AK, Xiang X, Ruderman NB (2005) AMPK, the metabolic syndrome and cancer. Trends Pharmacol Sci 26:69–76.PubMedCrossRefGoogle Scholar
  42. Mamane Y, Petroulakis E, LeBacquer O, Sonenberg N (2006) mTOR, translation initiation and cancer. Oncogene 25:6416–6422.PubMedCrossRefGoogle Scholar
  43. Mohr I (2006) Phosphorylation and dephosphorylation events that regulate viral mRNA translation. Virus Res 119:89–99.PubMedCrossRefGoogle Scholar
  44. Mumby M (2007) The 3D structure of protein phosphatase 2A: new insights into a ubiquitous regulator of cell signaling. ACS Chem Biol 2:99–103.PubMedCrossRefGoogle Scholar
  45. Plas DR, Thompson CB (2005) Akt-dependent transformation: there is more to growth than just surviving. Oncogene 24:7435–7442.PubMedCrossRefGoogle Scholar
  46. Polak P, Hall MN (2006) mTORC2 Caught in a SINful Akt. Dev Cell 11:433–434.PubMedCrossRefGoogle Scholar
  47. Reiling JH, Sabatini DM (2006) Stress and mTORture signaling. Oncogene 25:6373–6383.PubMedCrossRefGoogle Scholar
  48. Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH (1994) RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78:35–43.PubMedCrossRefGoogle Scholar
  49. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14:1296–1302.PubMedCrossRefGoogle Scholar
  50. Sarbassov DD, Ali SM, Sabatini DM (2005a) Growing roles for the mTOR pathway. Curr Opin Cell Biol 17:596–603.PubMedCrossRefGoogle Scholar
  51. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005b) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098–1101.PubMedCrossRefGoogle Scholar
  52. Schwarzer R, Tondera D, Arnold W, Giese K, Klippel A, Kaufmann J (2005) REDD1 integrates hypoxia-mediated survival signaling downstream of phosphatidylinositol 3-kinase. Oncogene 24:1138–1149.PubMedCrossRefGoogle Scholar
  53. Sharon-Friling R, Goodhouse J, Colberg-Poley AM, Shenk T (2006) Human cytomegalovirus pUL37×1 induces the release of endoplasmic reticulum calcium stores. Proc Natl Acad Sci U S A 130:19117–19122.CrossRefGoogle Scholar
  54. Shaw RJ, Bardeesy N, Manning BD, Lopez L, Kosmatka M, DePinho RA, Cantley LC (2004) The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6:91–99.PubMedCrossRefGoogle Scholar
  55. Shen YH, Zhang L, Utama B, Wang J, Gan Y, Wang X, Wang J, Chen L, Vercellotti GM, Coselli JS, Mehta JL, Wang XL (2006) Human cytomegalovirus inhibits Akt-mediated eNOS activation through upregulating PTEN (phosphatase and tensin homolog deleted on chromosome 10). Cardiovasc Res 69:502–511.PubMedCrossRefGoogle Scholar
  56. Summers SA, Garza LA, Zhou H, Birnbaum MJ (1998) Regulation of insulin-stimulated glucose transporter GLUT4 translocation and Akt kinase activity by ceramide. Mol Cell Biol 18:5457–5464.PubMedGoogle Scholar
  57. Ueki K, Yamamoto-Honda R, Kaburagi Y, Yamauchi T, Tobe K, Burgering BM, Coffer PJ, Komuro I, Akanuma Y, Yazaki Y, Kadowaki T (1998) Potential role of protein kinase B in insulin-induced glucose transport, glycogen synthesis, and protein synthesis. J Biol Chem 273:5315–5322.PubMedCrossRefGoogle Scholar
  58. van den Beucken T, Koritzinsky M, Wouters BG (2006) Translational control of gene expression during hypoxia. Cancer Biol Therapy 5:749–755.Google Scholar
  59. Vezina C, Kudelski A, Sehgal SN (1975) Rapamycin (AY-22, 989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiotics 28:721–726.Google Scholar
  60. Walsh D, Perez C, Notary J, Mohr I (2005) Regulation of the translation initiation factor eIF4F by multiple mechanisms in human cytomegalovirus-infected cells. J Virol 79:8057–8064.PubMedCrossRefGoogle Scholar
  61. Wek RC, Jiang HY, Anthony TG (2006) Coping with stress: eIF2 kinases and translational control. Biochem Soc Trans 34:7–11.PubMedCrossRefGoogle Scholar
  62. Wouters BG, van den Beucken T, Magagnin MG, Koritzinsky M, Fels D, Koumenis C (2005) Control of the hypoxic response through regulation of mRNA translation. Sem Cell Dev Biol 16:487–501.CrossRefGoogle Scholar
  63. Yang Q, Inoki K, Ikenoue T, Guan K-L, Iaccheri L (2006a) Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes Dev 20:2820–2832.PubMedCrossRefGoogle Scholar
  64. Yang Q, Inoki K, Kim E, Guan K-L (2006b) TSC1/TSC2 and Rheb have different effects on TORC1 and TORC2 activity. Proc Natl Acad Sci U S A 103:6811–6816.PubMedCrossRefGoogle Scholar
  65. Yu Y, Alwine JC (2002) 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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  • J. C. Alwine
    • 1
  1. 1.Department of Cancer BiologyUniversity of PennsylvaniaPhiladelphiaUSA

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