Inhibition of mTORC1 Enhances the Translation of Chikungunya Proteins the Activation of the MnK/eIF4E Pathway

English version České info

The ongoing chikungunya epidemic outbreak in the Caribbean, Central and South America highlights how poor is our understanding of CHIKV pathogenesis and the urgent need for new strategies that may limit CHIKV spread. Immunological studies have suggested that dissemination of infection is largely determined by early events of viral-host cell interactions. In our prior study, we investigated the role of type I interferon responses and the autophagy pathway as mediators of viral control. Here, we evaluated the role of mTOR, making the surprising discovery that inhibition of mTORC1 enhances viral protein translation independently of type I IFN and autophagy. While the inhibition of mTORC1 has no impact on viral binding or entry, we observed an increased translation of both structural and nonstructural viral proteins. Interestingly, the positive impact of mTORC1 inhibition is restricted to viral proteins, as compared to host cap-dependent protein translation that remains suppressed. Further analysis demonstrates that this bypass pathway is mediated the activation of PI3K and MnKs, which in turn hyper-phosphorylate eIF4E, a critical initiation protein for translation. Notably, CHIKV replication enables this pathway as a means to efficiently replicate. Thus, our study provides an unexpected role for mTORC1 in the control of CHIKV infection and highlights a new strategy by which the expression of CHIKV proteins can bypass and/or use the inhibition of mTORC1.

Vyšlo v časopise: Inhibition of mTORC1 Enhances the Translation of Chikungunya Proteins the Activation of the MnK/eIF4E Pathway. PLoS Pathog 11(8): e32767. doi:10.1371/journal.ppat.1005091
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005091

Souhrn

Zdroje

1. The 2005–2007 Chikungunya epidemic in Réunion: ambiguous etiologies, memories, and meaning-making. (2013) The 2005–2007 Chikungunya epidemic in Réunion: ambiguous etiologies, memories, and meaning-making. 32: 174–189. Available: http://www.tandfonline.com/doi/abs/10.1080/01459740.2012.679981. doi: 10.1080/01459740.2012.679981 23406067

2. Chikungunya outbreak in bueng kan province, Thailand, 2013. (2014) Chikungunya outbreak in bueng kan province, Thailand, 2013. 20: 1404–1406. Available: http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=25061989&retmode=ref&cmd=prlinks. doi: 10.3201/eid2008.140481 25061989

3. Re-emergence of chikungunya virus. (2014) Re-emergence of chikungunya virus.: JVI.01432–14. Available: http://jvi.asm.org/cgi/doi/10.1128/JVI.01432-14.

4. Notes from the field: chikungunya virus spreads in the Americas—Caribbean and South America, 2013–2014. (2014) Notes from the field: chikungunya virus spreads in the Americas—Caribbean and South America, 2013–2014. 63: 500–501. Available: http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=24898168&retmode=ref&cmd=prlinks.

5. Proteomic analysis of chikungunya virus infected microgial cells. (2012) Proteomic analysis of chikungunya virus infected microgial cells. 7: e34800. Available: http://dx.plos.org/10.1371/journal.pone.0034800. doi: 10.1371/journal.pone.0034800 22514668

6. An in vitro assay to study chikungunya virus RNA synthesis and the mode of action of inhibitors. (2014) An in vitro assay to study chikungunya virus RNA synthesis and the mode of action of inhibitors.: vir.0.069690–vir.0.069690. Available: http://vir.sgmjournals.org/content/early/2014/08/17/vir.0.069690-0.abstract.

7. Chikungunya virus and prospects for a vaccine. (2012) Chikungunya virus and prospects for a vaccine. 11: 1087–1101. Available: http://informahealthcare.com/doi/abs/10.1586/erv.12.84. doi: 10.1586/erv.12.84 23151166

8. Krejbich-Trotot P, Denizot M, Hoarau JJ, Jaffar-Bandjee MC, Das T, et al. (2011) Chikungunya virus mobilizes the apoptotic machinery to invade host cell defenses. The FASEB Journal 25: 314–325. doi: 10.1096/fj.10-164178 20881210

9. Joubert PE, Werneke SW, la Calle de C, Guivel-Benhassine F, Giodini A, et al. (2012) Chikungunya virus-induced autophagy delays caspase-dependent cell death. Journal of Experimental Medicine 209: 1029–1047. doi: 10.1084/jem.20110996 22508836

10. Influence of mTOR in energy and metabolic homeostasis. (2014) Influence of mTOR in energy and metabolic homeostasis. Available: http://linkinghub.elsevier.com/retrieve/pii/S0303720714002196.

11. mTORC2 in the center of cancer metabolic reprogramming. (2014) mTORC2 in the center of cancer metabolic reprogramming. 25: 364–373. Available: http://linkinghub.elsevier.com/retrieve/pii/S1043276014000721. doi: 10.1016/j.tem.2014.04.002 24856037

12. Martin S, Saha B, Riley JL (2012) The Battle over mTOR: An Emerging Theatre in Host–Pathogen Immunity. PLoS Pathog 8: e1002894–e1002895. doi: 10.1371/journal.ppat.1002894 23028309

13. Zhou X, Wang Y, Metselaar HJ, Janssen HLA, Peppelenbosch MP, et al. (2014) Rapamycin and everolimus facilitate hepatitis E virus replication: Revealing a basal defense mechanism of PI3K-PKB-mTOR pathway. JOURNAL OF HEPATOLOGY: 1–9. doi: 10.1016/j.jhep.2014.05.026

14. Hepatitis C virus activates the mTOR/S6K1 signaling pathway in inhibiting IRS-1 function for insulin resistance. (2012) Hepatitis C virus activates the mTOR/S6K1 signaling pathway in inhibiting IRS-1 function for insulin resistance. 86: 6315–6322. Available: http://jvi.asm.org/cgi/doi/10.1128/JVI.00050-12. doi: 10.1128/JVI.00050-12 22457523

15. Li Q, ne VERPE, Krishnamurthy S, Cha H, Liang TJ (2013) Hepatitis C virus infection activates an innate pathway involving IKK-α in lipogenesis and viral assembly. Nature Medicine 19: 722–729. doi: 10.1038/nm.3190 23708292

16. Type I IFN controls chikungunya virus via its action on nonhematopoietic cells. (2010) Type I IFN controls chikungunya virus via its action on nonhematopoietic cells. 207: 429–442. Available: http://www.jem.org/cgi/doi/10.1084/jem.20090851. doi: 10.1084/jem.20090851 20123960

17. RAPping production of type i interferon in pDCs through mTOR (2008) RAPping production of type i interferon in pDCs through mTOR: 1–3.

18. Herdy B, Jaramillo M, Svitkin YV, Rosenfeld AB, Kobayashi M, et al. (2012) Translational control of the activation of transcription factor NF-κB and production of type I interferon by phosphorylation of the translation factor eIF4E. Nature Immunology 13: 543–550. doi: 10.1038/ni.2291 22544393

19. Kinase mTOR: regulation and role in maintenance of cellular homeostasis, tumor development, and aging. (2014) Kinase mTOR: regulation and role in maintenance of cellular homeostasis, tumor development, and aging. 79: 88–101. Available: http://link.springer.com/10.1134/S0006297914020023. doi: 10.1134/S0006297914020023 24794724

20. Judith D, Mostowy S, Bourai M, Gangneux N, Lelek MEL, et al. (2013) Species-specific impact of the autophagy machinery on Chikungunya virus infection. Nature Publishing Group: 1–11. doi: 10.1038/embor.2013.51

21. Interferon response factors 3 and 7 protect against Chikungunya virus hemorrhagic fever and shock. (2012) Interferon response factors 3 and 7 protect against Chikungunya virus hemorrhagic fever and shock. 86: 9888–9898. Available: http://jvi.asm.org/cgi/doi/10.1128/JVI.00956-12. doi: 10.1128/JVI.00956-12 22761364

22. A mouse model for Chikungunya: young age and inefficient type-I interferon signaling are risk factors for severe disease. (2008) A mouse model for Chikungunya: young age and inefficient type-I interferon signaling are risk factors for severe disease. 4: e29. Available: http://dx.plos.org/10.1371/journal.ppat.0040029. doi: 10.1371/journal.ppat.0040029 18282093

23. Schmidt EK, Clavarino G, Ceppi M, Pierre P (2009) SUnSET, a nonradioactive method to monitor protein synthesis. Nat Meth 6: 275–277. doi: 10.1038/nmeth.1314

24. Structural and functional diversity of viral IRESes. (2009) Structural and functional diversity of viral IRESes. 1789: 542–557. Available: http://linkinghub.elsevier.com/retrieve/pii/S1874939909000820. doi: 10.1016/j.bbagrm.2009.07.005 19632368

25. eIF4E, the mRNA cap-binding protein: from basic discovery to translational research. (2008) eIF4E, the mRNA cap-binding protein: from basic discovery to translational research. 86: 178–183. Available: http://www.nrcresearchpress.com/doi/abs/10.1139/O08-034. doi: 10.1139/O08-034 18443631

26. Adaptation to chronic mTOR inhibition in cancer and in aging. (2013) Adaptation to chronic mTOR inhibition in cancer and in aging. 41: 956–961. Available: http://www.biochemsoctrans.org/bst/041/bst0410956.htm. doi: 10.1042/BST20130080 23863163

27. Cope CL, Gilley R, Balmanno K, Sale MJ, Howarth KD, et al. (2014) Adaptation to mTOR kinase inhibitors by amplification of eIF4E to maintain cap-dependent translation. Journal of Cell Science 127: 788–800. doi: 10.1242/jcs.137588 24363449

28. Phosphorylation of eIF4E by MNKs supports protein synthesis, cell cycle progression and proliferation in prostate cancer cells. (2008) Phosphorylation of eIF4E by MNKs supports protein synthesis, cell cycle progression and proliferation in prostate cancer cells. 29: 2279–2288. Available: http://www.carcin.oxfordjournals.org/cgi/doi/10.1093/carcin/bgn221. doi: 10.1093/carcin/bgn221 18809972

29. The oncogene eIF4E: using biochemical insights to target cancer. (2013) The oncogene eIF4E: using biochemical insights to target cancer. 33: 227–238. Available: http://online.liebertpub.com/doi/abs/10.1089/jir.2012.0142. doi: 10.1089/jir.2012.0142 23472659

30. Stead RL, Proud CG (2013) Rapamycin enhances eIF4E phosphorylation by activating MAP kinase-interacting kinase 2a (Mnk2a). FEBS Letters 587: 2623–2628. doi: 10.1016/j.febslet.2013.06.045 23831578

31. Grzmil M, Huber RM, Hess D, Frank S, Hynx D, et al. (2014) MNK1 pathway activity maintains protein synthesis in rapalog-treated gliomas. J Clin Invest 124: 742–754. doi: 10.1172/JCI70198 24401275

32. Wang X, Yue P, Chan CB, Ye K, Ueda T, et al. (2007) Inhibition of Mammalian Target of Rapamycin Induces Phosphatidylinositol 3-Kinase-Dependent and Mnk-Mediated Eukaryotic Translation Initiation Factor 4E Phosphorylation. Molecular and Cellular Biology 27: 7405–7413. doi: 10.1128/MCB.00760-07 17724079

33. McNulty S, Flint M, Nichol ST, Spiropoulou CF (2012) Host mTORC1 Signaling Regulates Andes Virus Replication. Journal of Virology 87: 912–922. doi: 10.1128/JVI.02415-12 23135723

34. Influenza virus mRNA translation revisited: is the eIF4E cap-binding factor required for viral mRNA translation? (2007) Influenza virus mRNA translation revisited: is the eIF4E cap-binding factor required for viral mRNA translation? 81: 12427–12438. Available: http://jvi.asm.org/cgi/doi/10.1128/JVI.01105-07. 17855553

35. Many roads from mTOR to eIF4F. (2013) Many roads from mTOR to eIF4F. 41: 913–916. Available: http://www.biochemsoctrans.org/bst/041/bst0410913.htm. doi: 10.1042/BST20130082 23863155

36. JOUBERT P-E, Werneke S, la Calle de C, Guivel-Benhassine F, Giodini A, et al. (2014) Chikungunya-induced cell death is limited by ER and oxidative stress-induced autophagy. Autophagy 8: 1261–1263. doi: 10.4161/auto.20751

37. Cao W, Manicassamy S, Tang H, Kasturi SP, Pirani A, et al. (2008) Toll-like receptor–mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway. Nature Immunology 9: 1157–1164. doi: 10.1038/ni.1645 18758466

38. Deretic V, Levine B (2009) Autophagy, Immunity, and Microbial Adaptations. Cell Host & Microbe 5: 527–549. doi: 10.1016/j.chom.2009.05.016

39. Blanchet FP, Moris A, Nikolic DS, Lehmann M, Cardinaud S, et al. (2010) Human Immunodeficiency Virus-1 Inhibition of Immunoamphisomes in Dendritic Cells Impairs Early Innate and Adaptive Immune Responses. Immunity 32: 654–669. doi: 10.1016/j.immuni.2010.04.011 20451412

40. Gad HH, Paulous S, Belarbi E, Diancourt L, Drosten C, et al. (2012) The E2-E166K substitution restores Chikungunya virus growth in OAS3 expressing cells by acting on viral entry. Virology 434: 27–37. doi: 10.1016/j.virol.2012.07.019 22889614

41. Chikungunya virus nonstructural protein 2 inhibits type I/II interferon-stimulated JAK-STAT signaling. (2010) Chikungunya virus nonstructural protein 2 inhibits type I/II interferon-stimulated JAK-STAT signaling. 84: 10877–10887. Available: http://jvi.asm.org/cgi/doi/10.1128/JVI.00949-10. doi: 10.1128/JVI.00949-10 20686047