Skip to main content
PMC home page
Journal of Virology logoLink to Journal of Virology
. 1996 Dec;70(12):8993–8996. doi: 10.1128/jvi.70.12.8993-8996.1996

Rapamycin stimulates viral protein synthesis and augments the shutoff of host protein synthesis upon picornavirus infection.

L Beretta 1, Y V Svitkin 1, N Sonenberg 1
PMCID: PMC190998  PMID: 8971030

Abstract

The immunosuppressant drug rapamycin blocks progression of the cell cycle at G1 in mammalian cells and yeast. We recently showed that rapamycin inhibits both in vitro and in vivo cap-dependent, but not cap-independent, translation. This inhibition is causally related to reduced phosphorylation and consequent activation of 4E-BP1, a repressor of the function of the cap-binding protein, eIF4E. Two members of the picornavirus family, encephalomyocarditis virus and poliovirus, inhibit phosphorylation of 4E-BP1. Since translation of picornavirus mRNAs is cap independent, inhibition of phosphorylation of 4E-BP1 could contribute to the shutoff of host protein synthesis. Here, we show that rapamycin augments both the shutoff of host protein synthesis and the initial rate of synthesis of viral proteins in cells infected with encephalomyocarditis virus and poliovirus.

Full Text

The Full Text of this article is available as a PDF (336.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abreu S. L., Lucas-Lenard J. Cellular protein synthesis shutoff by mengovirus: translation of nonviral and viral mRNA's in extracts from uninfected and infected Ehrlich ascites tumor cells. J Virol. 1976 Apr;18(1):182–194. doi: 10.1128/jvi.18.1.182-194.1976. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barbet N. C., Schneider U., Helliwell S. B., Stansfield I., Tuite M. F., Hall M. N. TOR controls translation initiation and early G1 progression in yeast. Mol Biol Cell. 1996 Jan;7(1):25–42. doi: 10.1091/mbc.7.1.25. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Beretta L., Gingras A. C., Svitkin Y. V., Hall M. N., Sonenberg N. Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initiation of translation. EMBO J. 1996 Feb 1;15(3):658–664. [PMC free article] [PubMed] [Google Scholar]
  4. Brown E. J., Albers M. W., Shin T. B., Ichikawa K., Keith C. T., Lane W. S., Schreiber S. L. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature. 1994 Jun 30;369(6483):756–758. doi: 10.1038/369756a0. [DOI] [PubMed] [Google Scholar]
  5. Gingras A. C., Svitkin Y., Belsham G. J., Pause A., Sonenberg N. Activation of the translational suppressor 4E-BP1 following infection with encephalomyocarditis virus and poliovirus. Proc Natl Acad Sci U S A. 1996 May 28;93(11):5578–5583. doi: 10.1073/pnas.93.11.5578. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Graves L. M., Bornfeldt K. E., Argast G. M., Krebs E. G., Kong X., Lin T. A., Lawrence J. C., Jr cAMP- and rapamycin-sensitive regulation of the association of eukaryotic initiation factor 4E and the translational regulator PHAS-I in aortic smooth muscle cells. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7222–7226. doi: 10.1073/pnas.92.16.7222. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Haghighat A., Mader S., Pause A., Sonenberg N. Repression of cap-dependent translation by 4E-binding protein 1: competition with p220 for binding to eukaryotic initiation factor-4E. EMBO J. 1995 Nov 15;14(22):5701–5709. doi: 10.1002/j.1460-2075.1995.tb00257.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Heitman J., Movva N. R., Hall M. N. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science. 1991 Aug 23;253(5022):905–909. doi: 10.1126/science.1715094. [DOI] [PubMed] [Google Scholar]
  9. Helentjaris T., Ehrenfeld E. Control of protein synthesis in extracts from poliovirus-infected cells. I. mRNA discrimination by crude initiation factors. J Virol. 1978 May;26(2):510–521. doi: 10.1128/jvi.26.2.510-521.1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hu C., Pang S., Kong X., Velleca M., Lawrence J. C., Jr Molecular cloning and tissue distribution of PHAS-I, an intracellular target for insulin and growth factors. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3730–3734. doi: 10.1073/pnas.91.9.3730. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Jackson R. J., Howell M. T., Kaminski A. The novel mechanism of initiation of picornavirus RNA translation. Trends Biochem Sci. 1990 Dec;15(12):477–483. doi: 10.1016/0968-0004(90)90302-r. [DOI] [PubMed] [Google Scholar]
  12. Jang S. K., Kräusslich H. G., Nicklin M. J., Duke G. M., Palmenberg A. C., Wimmer E. A segment of the 5' nontranslated region of encephalomyocarditis virus RNA directs internal entry of ribosomes during in vitro translation. J Virol. 1988 Aug;62(8):2636–2643. doi: 10.1128/jvi.62.8.2636-2643.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kaufmann Y., Goldstein E., Penman S. Poliovirus-induced inhibition of polypeptide initiation in vitro on native polyribosomes. Proc Natl Acad Sci U S A. 1976 Jun;73(6):1834–1838. doi: 10.1073/pnas.73.6.1834. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kunz J., Henriquez R., Schneider U., Deuter-Reinhard M., Movva N. R., Hall M. N. Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. Cell. 1993 May 7;73(3):585–596. doi: 10.1016/0092-8674(93)90144-f. [DOI] [PubMed] [Google Scholar]
  15. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  16. Leibowitz R., Penman S. Regulation of protein synthesis in HeLa cells. 3. Inhibition during poliovirus infection. J Virol. 1971 Nov;8(5):661–668. doi: 10.1128/jvi.8.5.661-668.1971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lin T. A., Kong X., Haystead T. A., Pause A., Belsham G., Sonenberg N., Lawrence J. C., Jr PHAS-I as a link between mitogen-activated protein kinase and translation initiation. Science. 1994 Oct 28;266(5185):653–656. doi: 10.1126/science.7939721. [DOI] [PubMed] [Google Scholar]
  18. Lin T. A., Kong X., Saltiel A. R., Blackshear P. J., Lawrence J. C., Jr Control of PHAS-I by insulin in 3T3-L1 adipocytes. Synthesis, degradation, and phosphorylation by a rapamycin-sensitive and mitogen-activated protein kinase-independent pathway. J Biol Chem. 1995 Aug 4;270(31):18531–18538. doi: 10.1074/jbc.270.31.18531. [DOI] [PubMed] [Google Scholar]
  19. Mader S., Lee H., Pause A., Sonenberg N. The translation initiation factor eIF-4E binds to a common motif shared by the translation factor eIF-4 gamma and the translational repressors 4E-binding proteins. Mol Cell Biol. 1995 Sep;15(9):4990–4997. doi: 10.1128/mcb.15.9.4990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Pause A., Belsham G. J., Gingras A. C., Donzé O., Lin T. A., Lawrence J. C., Jr, Sonenberg N. Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function. Nature. 1994 Oct 27;371(6500):762–767. doi: 10.1038/371762a0. [DOI] [PubMed] [Google Scholar]
  21. Pelletier J., Sonenberg N. Internal initiation of translation of eukaryotic mRNA directed by a sequence derived from poliovirus RNA. Nature. 1988 Jul 28;334(6180):320–325. doi: 10.1038/334320a0. [DOI] [PubMed] [Google Scholar]
  22. Sabatini D. M., Erdjument-Bromage H., Lui M., Tempst P., Snyder S. H. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell. 1994 Jul 15;78(1):35–43. doi: 10.1016/0092-8674(94)90570-3. [DOI] [PubMed] [Google Scholar]
  23. Sabers C. J., Martin M. M., Brunn G. J., Williams J. M., Dumont F. J., Wiederrecht G., Abraham R. T. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem. 1995 Jan 13;270(2):815–822. doi: 10.1074/jbc.270.2.815. [DOI] [PubMed] [Google Scholar]
  24. Sonenberg N. Regulation of translation by poliovirus. Adv Virus Res. 1987;33:175–204. doi: 10.1016/s0065-3527(08)60318-8. [DOI] [PubMed] [Google Scholar]
  25. Stan R., McLaughlin M. M., Cafferkey R., Johnson R. K., Rosenberg M., Livi G. P. Interaction between FKBP12-rapamycin and TOR involves a conserved serine residue. J Biol Chem. 1994 Dec 23;269(51):32027–32030. [PubMed] [Google Scholar]
  26. Svitkin Y. V., Ginevskaya V. A., Ugarova T. Y., Agol V. I. A cell-free model of the encephalomyocarditis virus-induced inhibition of host cell protein synthesis. Virology. 1978 Jun 1;87(1):199–203. doi: 10.1016/0042-6822(78)90172-1. [DOI] [PubMed] [Google Scholar]
  27. Svitkin Y. V., Ugarova T. Y., Ginevskaya V. A., Kalinina N. O., Scarlat I. V., Agol V. I. Efficiency of translation of viral and cellular mRNA's in extracts from cells infected with encephalomyocarditis virus. Intervirology. 1974;4(4):214–220. doi: 10.1159/000149965. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES