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Modulation of Host Cell Stress Responses by Human Cytomegalovirus

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Book cover Human Cytomegalovirus

Part of the book series: Current Topics in Microbiology and Immunology ((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.

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References

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Baker SJ (2007) PTEN enters the nuclear age. Cell 128:25–28.

    Article  PubMed  CAS  Google Scholar 

  • Banaszynski LA, Liu CW, Wandless TJ (2005) Characterization of the FKBP-rapamycin-FRB ternary complex. J Am Chem Soc 127:4715–4721.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Bjornsti MA, Houghton PJ (2004) The TOR pathway: a target for cancer therapy. Nat Rev Cancer 4:335–348.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Datta SR, Brunet A, Greenberg ME (1999) Cellular survival: a play in three Akts. Genes Dev 13:2905–2927.

    Article  PubMed  CAS  Google Scholar 

  • Hakki M, Geballe AP (2005) Double-stranded RNA binding by human cytomegalovirus pTRS1. J Virol 79:7311–7318.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Hardie DG (2007) AMP-activated protein kinase as a drug target. Annu Rev Pharmacol Toxicol 47:185–210.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Isler JA, Skalet AH, Alwine JC (2005b) Human cytomegalovirus infection activates and regulates the unfolded protein response. J Virol 79:6890–6899.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Kimble SR (2006) Interaction between the AMP-activated protein kinase and mTOR signaling pathways. Med Sci Sports Exercise 38:1958–1964.

    Article  Google Scholar 

  • Knudson AG (1988) The genetics of childhood cancer. Bull Cancer 73:135–138.

    Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Luo Z, Saha AK, Xiang X, Ruderman NB (2005) AMPK, the metabolic syndrome and cancer. Trends Pharmacol Sci 26:69–76.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Mohr I (2006) Phosphorylation and dephosphorylation events that regulate viral mRNA translation. Virus Res 119:89–99.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Plas DR, Thompson CB (2005) Akt-dependent transformation: there is more to growth than just surviving. Oncogene 24:7435–7442.

    Article  PubMed  CAS  Google Scholar 

  • Polak P, Hall MN (2006) mTORC2 Caught in a SINful Akt. Dev Cell 11:433–434.

    Article  PubMed  CAS  Google Scholar 

  • Reiling JH, Sabatini DM (2006) Stress and mTORture signaling. Oncogene 25:6373–6383.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Sarbassov DD, Ali SM, Sabatini DM (2005a) Growing roles for the mTOR pathway. Curr Opin Cell Biol 17:596–603.

    Article  PubMed  CAS  Google Scholar 

  • Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005b) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098–1101.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • van den Beucken T, Koritzinsky M, Wouters BG (2006) Translational control of gene expression during hypoxia. Cancer Biol Therapy 5:749–755.

    Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Wek RC, Jiang HY, Anthony TG (2006) Coping with stress: eIF2 kinases and translational control. Biochem Soc Trans 34:7–11.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Cancer Biology, University of Pennsylvania, 19014, Philadelphia, PA, USA

    J. C. Alwine

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  1. J. C. Alwine
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Editors and Affiliations

  1. Princeton University, 08544-1014, Princeton, NJ, USA

    Thomas E. Shenk

  2. University of Iowa, 52242, Iowa, IA, USA

    Mark F. Stinski

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© 2008 Springer-Verlag Berlin Heidelberg

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Alwine, J.C. (2008). Modulation of Host Cell Stress Responses by Human Cytomegalovirus. In: Shenk, T.E., Stinski, M.F. (eds) Human Cytomegalovirus. Current Topics in Microbiology and Immunology, vol 325. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-77349-8_15

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