Translation of Viral MRNAs That Do Not Require EIF4E is Blocked by the Inhibitor 4EGI-1

Overview

Journal Virology

Specialty Microbiology

Date 2013 Jul 23

PMID 23870416

Citations 6

Authors

Natalia Redondo

Manuel Garcia-Moreno

Miguel Angel Sanz

Luis Carrasco

Affiliations

Soon will be listed here.

Abstract

High throughput screening has rendered new inhibitors of eukaryotic protein synthesis. One such molecule, 4EGI-1 has been reported to selectively block the initiation factor eIF4E. We have investigated the action of this inhibitor on translation directed by several viral mRNAs which, in principle, do not utilize eIF4E. We found that 4EGI-1 inhibits translation directed by poliovirus IRES, in rabbit reticulocyte lysates, to a similar extent as capped mRNA. Moreover, 4EGI-1 inhibits translation driven by poliovirus IRES, both in vitro and in cultured cells, despite cleavage of eIF4G by picornavirus proteases. Finally, translation of vesicular stomatitis virus mRNAs and Sindbis virus subgenomic mRNA is blocked by 4EGI-1 in infected cells to a similar extent as cellular mRNAs. These findings cast doubt on the selective action of this inhibitor, and suggest that this molecule may affect other steps in protein synthesis unrelated to cap recognition by eIF4E.

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References

Deniz N, Lenarcic E, Landry D, Thompson S . Translation initiation factors are not required for Dicistroviridae IRES function in vivo. RNA. 2009; 15(5):932-46. PMC: 2673076. DOI: 10.1261/rna.1315109. View

Lorsch J, Dever T . Molecular view of 43 S complex formation and start site selection in eukaryotic translation initiation. J Biol Chem. 2010; 285(28):21203-7. PMC: 2898419. DOI: 10.1074/jbc.R110.119743. View

Alvarez E, Menendez-Arias L, Carrasco L . The eukaryotic translation initiation factor 4GI is cleaved by different retroviral proteases. J Virol. 2003; 77(23):12392-400. PMC: 262572. DOI: 10.1128/jvi.77.23.12392-12400.2003. View

Hundsdoerfer P, Thoma C, Hentze M . Eukaryotic translation initiation factor 4GI and p97 promote cellular internal ribosome entry sequence-driven translation. Proc Natl Acad Sci U S A. 2005; 102(38):13421-6. PMC: 1224658. DOI: 10.1073/pnas.0506536102. View

Descamps G, Gomez-Bougie P, Tamburini J, Green A, Bouscary D, Maiga S . The cap-translation inhibitor 4EGI-1 induces apoptosis in multiple myeloma through Noxa induction. Br J Cancer. 2012; 106(10):1660-7. PMC: 3349175. DOI: 10.1038/bjc.2012.139. View

Richter J, Sonenberg N . Regulation of cap-dependent translation by eIF4E inhibitory proteins. Nature. 2005; 433(7025):477-80. DOI: 10.1038/nature03205. View

Vazquez D . Inhibitors of protein biosynthesis. Mol Biol Biochem Biophys. 1979; 30:i-x, 1-312. DOI: 10.1007/978-3-642-81309-2. View

Chen L, Aktas B, Wang Y, He X, Sahoo R, Zhang N . Tumor suppression by small molecule inhibitors of translation initiation. Oncotarget. 2012; 3(8):869-81. PMC: 3478463. DOI: 10.18632/oncotarget.598. View

Jackson R, Hellen C, Pestova T . The mechanism of eukaryotic translation initiation and principles of its regulation. Nat Rev Mol Cell Biol. 2010; 11(2):113-27. PMC: 4461372. DOI: 10.1038/nrm2838. View

10.

Castello A, Sanz M, Molina S, Carrasco L . Translation of Sindbis virus 26S mRNA does not require intact eukariotic initiation factor 4G. J Mol Biol. 2005; 355(5):942-56. DOI: 10.1016/j.jmb.2005.11.024. View

11.

Santini E, Huynh T, MacAskill A, Carter A, Pierre P, Ruggero D . Exaggerated translation causes synaptic and behavioural aberrations associated with autism. Nature. 2012; 493(7432):411-5. PMC: 3548017. DOI: 10.1038/nature11782. View

12.

Hoeffer C, Cowansage K, Arnold E, L Banko J, Moerke N, Rodriguez R . Inhibition of the interactions between eukaryotic initiation factors 4E and 4G impairs long-term associative memory consolidation but not reconsolidation. Proc Natl Acad Sci U S A. 2011; 108(8):3383-8. PMC: 3044415. DOI: 10.1073/pnas.1013063108. View

13.

Cencic R, Hall D, Robert F, Du Y, Min J, Li L . Reversing chemoresistance by small molecule inhibition of the translation initiation complex eIF4F. Proc Natl Acad Sci U S A. 2010; 108(3):1046-51. PMC: 3024666. DOI: 10.1073/pnas.1011477108. View

14.

Connor J, Lyles D . Vesicular stomatitis virus infection alters the eIF4F translation initiation complex and causes dephosphorylation of the eIF4E binding protein 4E-BP1. J Virol. 2002; 76(20):10177-87. PMC: 136556. DOI: 10.1128/jvi.76.20.10177-10187.2002. View

15.

Castello A, Alvarez E, Carrasco L . The multifaceted poliovirus 2A protease: regulation of gene expression by picornavirus proteases. J Biomed Biotechnol. 2011; 2011:369648. PMC: 3085340. DOI: 10.1155/2011/369648. View

16.

Sanz M, Welnowska E, Redondo N, Carrasco L . Translation driven by picornavirus IRES is hampered from Sindbis virus replicons: rescue by poliovirus 2A protease. J Mol Biol. 2010; 402(1):101-17. DOI: 10.1016/j.jmb.2010.07.014. View

17.

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; 15(9):4990-7. PMC: 230746. DOI: 10.1128/MCB.15.9.4990. View

18.

Sanz M, Castello A, Ventoso I, Berlanga J, Carrasco L . Dual mechanism for the translation of subgenomic mRNA from Sindbis virus in infected and uninfected cells. PLoS One. 2009; 4(3):e4772. PMC: 2651626. DOI: 10.1371/journal.pone.0004772. View

19.

Bordeleau M, Mori A, Oberer M, Lindqvist L, Chard L, Higa T . Functional characterization of IRESes by an inhibitor of the RNA helicase eIF4A. Nat Chem Biol. 2006; 2(4):213-20. DOI: 10.1038/nchembio776. View

20.

Welnowska E, Sanz M, Redondo N, Carrasco L . Translation of viral mRNA without active eIF2: the case of picornaviruses. PLoS One. 2011; 6(7):e22230. PMC: 3136507. DOI: 10.1371/journal.pone.0022230. View