Influenza A Virus Host Shutoff Disables Antiviral Stress-Induced Translation Arrest

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Like all viruses, Influenza A virus (IAV) is absolutely dependent on host-cell protein synthesis machinery. This dependence makes the virus vulnerable to the innate ability of cells to inhibit protein synthesis in response to various types of stress. This inhibition, termed translation arrest, helps cells survive adverse conditions by re-dedicating their energy to stress responses. When cells arrest translation, they form stress granules: depots of untranslated mRNAs and associated proteins. Translation arrest and formation of stress granules can be induced pharmacologically, and in this work we sought to determine whether stress granule induction would be effective in blocking IAV replication. Here we demonstrate that treatment of cells with inducers of stress granules at early times after infection resulted in blockade of viral protein synthesis and stopped viral replication. At later times post-infection, by contrast, IAV proteins prevented pharmacological induction of stress granules. We identified three viral proteins –⁠ more than in any virus to date –⁠ that work in concert to prevent stress granule formation. Taken together, our studies reveal a multipronged approach for viral suppression of translation arrest, and identify a window of opportunity early in infection when pharmacological induction of stress granules has a strong antiviral effect.

Vyšlo v časopise: Influenza A Virus Host Shutoff Disables Antiviral Stress-Induced Translation Arrest. PLoS Pathog 10(7): e32767. doi:10.1371/journal.ppat.1004217
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004217

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Zdroje

1. PlotchSJ, BouloyM, UlmanenI, KrugRM (1981) A unique cap(m7GpppXm)-dependent influenza virion endonuclease cleaves capped RNAs to generate the primers that initiate viral RNA transcription. Cell 23 : 847–858.

2. NemeroffME, BarabinoSM, LiY, KellerW, KrugRM (1998) Influenza virus NS1 protein interacts with the cellular 30 kDa subunit of CPSF and inhibits 3′end formation of cellular pre-mRNAs. Mol Cell 1 : 991–1000.

3. YángüezE, NietoA (2011) So similar, yet so different: selective translation of capped and polyadenylated viral mRNAs in the influenza virus infected cell. Virus Res 156 : 1–12.

4. JaggerBW, WiseHM, KashJC, WaltersKK-A, WillsNM, et al. (2012) An overlapping protein-coding region in influenza A virus segment 3 modulates the host response. Science (80-) 165 : 199–204.

5. YamasakiS, AndersonP (2008) Reprogramming mRNA translation during stress. Curr Opin Cell Biol 20 : 222–226.

6. KedershaN, AndersonP (2007) Mammalian stress granules and processing bodies. Methods Enzymol 431 : 61–81.

7. WhiteJP, LloydRE (2012) Regulation of stress granules in virus systems. Trends Microbiol 20 : 175–183.

8. KhaperskyyDA, HatchetteTF, McCormickC (2012) Influenza A virus inhibits cytoplasmic stress granule formation. FASEB J 26 : 1629–1639.

9. CovarrubiasS, RichnerJM, ClydeK, LeeYJ, GlaunsingerBa (2009) Host shutoff is a conserved phenotype of gammaherpesvirus infection and is orchestrated exclusively from the cytoplasm. J Virol 83 : 9554–9566.

10. HarbM, BeckerMM, VitourD, BaronCH, VendeP, et al. (2008) Nuclear localization of cytoplasmic poly(A)-binding protein upon rotavirus infection involves the interaction of NSP3 with eIF4G and RoXaN. J Virol 82 : 11283–11293.

11. BlakqoriG, van KnippenbergI, ElliottRM (2009) Bunyamwera orthobunyavirus S-segment untranslated regions mediate poly(A) tail-independent translation. J Virol 83 : 3637–3646.

12. McEwenE, KedershaN, SongB, ScheunerD, GilksN, et al. (2005) Heme-regulated inhibitor kinase-mediated phosphorylation of eukaryotic translation initiation factor 2 inhibits translation, induces stress granule formation, and mediates survival upon arsenite exposure. J Biol Chem 280 : 16925–16933.

13. WatanabeK, TakizawaN, KatohM, HoshidaK, KobayashiN, et al. (2001) Inhibition of nuclear export of ribonucleoprotein complexes of influenza virus by leptomycin B. Virus Res 77 : 31–42.

14. AfoninaE, StauberR, PavlakisGN (1998) The human poly(A)-binding protein 1 shuttles between the nucleus and the cytoplasm. J Biol Chem 273 : 13015–13021.

15. MazrouiR, SukariehR, BordeleauM, KaufmanRJ, NorthcoteP, et al. (2006) Inhibition of Ribosome Recruitment Induces Stress Granule Formation Independently of Eukaryotic Initiation Factor 2 alpha Phosphorylation. Mol Biol Cell 17 : 4212–4219.

16. DengT, EngelhardtOG, ThomasB, AkoulitchevAV, BrownleeGG, et al. (2006) Role of ran binding protein 5 in nuclear import and assembly of the influenza virus RNA polymerase complex. J Virol 80 : 11911–11919.

17. OnomotoK, JogiM, YooJ-S, NaritaR, MorimotoS, et al. (2012) Critical role of an antiviral stress granule containing RIG-I and PKR in viral detection and innate immunity. PLoS One 7: e43031.

18. PortelaA, DigardP (2002) The influenza virus nucleoprotein: a multifunctional RNA-binding protein pivotal to virus replication. J Gen Virol 83 : 723–734.

19. EltonD, MedcalfE, BishopK, DigardP (1999) Oligomerization of the influenza virus nucleoprotein: identification of positive and negative sequence elements. Virology 260 : 190–200.

20. YeQ, KrugRM, TaoYJ (2006) The mechanism by which influenza A virus nucleoprotein forms oligomers and binds RNA. Nature 444 : 1078–1082.

21. WangP, PaleseP, O'NeillRE (1997) The NPI-1/NPI-3 (karyopherin alpha) binding site on the influenza a virus nucleoprotein NP is a nonconventional nuclear localization signal. J Virol 71 : 1850–1856.

22. MayerD, MolawiK, Martínez-sobridoL, GhanemA, BaginskyS, et al. (2008) Identification of cellular interaction partners of the influenza virus ribonucleoprotein complex and polymerase complex using proteomic-based approaches. J Proteome Res 6 : 672–682.

23. DesmetEa, BusseyKa, StoneR, TakimotoT (2013) Identification of the N-terminal domain of the influenza virus PA responsible for the suppression of host protein synthesis. J Virol 87 : 3108–3118.

24. KedershaN, ChenS, GilksN, LiW, MillerIJ, et al. (2002) Evidence That Ternary Complex (eIF2-GTP-tRNAiMet) –⁠ Deficient Preinitiation Complexes Are Core Constituents of Mammalian Stress Granules. Mol Biol Cell 13 : 195–210.

25. BordeleauM-E, MatthewsJ, WojnarJM, LindqvistL, NovacO, et al. (2005) Stimulation of mammalian translation initiation factor eIF4A activity by a small molecule inhibitor of eukaryotic translation. Proc Natl Acad Sci U S A 102 : 10460–10465.

26. JorbaN, ColomaR, OrtínJ (2009) Genetic trans-complementation establishes a new model for influenza virus RNA transcription and replication. PLoS Pathog 5: e1000462.

27. HatadaE, HasegawaM, MukaigawaJ, ShimizuK, FukudaR (1989) Control of influenza virus gene expression: quantitative analysis of each viral RNA species in infected cells. J Biochem 105 : 537–546.

28. Di MarcoS, CammasA, LianXJ, KovacsEN, MaJF, et al. (2012) The translation inhibitor pateamine A prevents cachexia-induced muscle wasting in mice. Nat Commun 3 : 896.

29. GlaunsingerB, ChavezL, GanemD (2005) The exonuclease and host shutoff functions of the SOX protein of Kaposi's sarcoma-associated herpesvirus are genetically separable. J Virol 79 : 7396–7401.

30. LeeYJ, GlaunsingerBA (2009) Aberrant herpesvirus-induced polyadenylation correlates with cellular messenger RNA destruction. PLoS Biol 7: e1000107.

31. KumarGR, ShumL, GlaunsingerBA (2011) Importin alpha-mediated nuclear import of cytoplasmic poly(A) binding protein occurs as a direct consequence of cytoplasmic mRNA depletion. Mol Cell Biol 31 : 3113–3125.

32. OhnT, KedershaN, HickmanT, TisdaleS, AndersonP (2008) A functional RNAi screen links O-GlcNAc modification of ribosomal proteins to stress granule and processing body assembly. Nat Cell Biol 10 : 1224–1231.

33. BaudinF, BachC, CusackS, RuigrokRW (1994) Structure of influenza virus RNP. I. Influenza virus nucleoprotein melts secondary structure in panhandle RNA and exposes the bases to the solvent. EMBO J 13 : 3158–3165.

34. YamanakaK, IshihamaA, NagataK (1990) Reconstitution of influenza virus RNA-nucleoprotein complexes structurally resembling native viral ribonucleoprotein cores. J Biol Chem 265 : 11151–11155.

35. LiZ, WatanabeT, HattaM, WatanabeS, NanboA, et al. (2009) Mutational analysis of conserved amino acids in the influenza A virus nucleoprotein. J Virol 83 : 4153–4162.

36. MokB, SongW, WangP, TaiH, ChenY, et al. (2012) The NS1 protein of influenza A virus interacts with cellular processing bodies and stress granules through RNA-associated protein 55 (RAP55) during virus infection. J Virol 86 : 12695–12707.

37. ZhouZ, CaoM, GuoY, ZhaoL, WangJ, et al. (2014) Fragile X mental retardation protein stimulates ribonucleoprotein assembly of influenza A virus. Nature Communications 5 : 3259.

38. WenX, HuangX, MokB, ChenY, ZhengM, et al. (2014) NF90 exerts antiviral activity through regulation of PKR phosphorylation and stress granules in infected cells. J Immunol 192 : 3753–3764.

39. LindqvistL, PelletierJ (2009) Inhibitors of translation initiation as cancer therapeutics. Future Med Chem 1 : 1709–1722.

40. KuznetsovG, XuQ, Rudolph-OwenL, TendykeK, LiuJ, et al. (2009) Potent in vitro and in vivo anticancer activities of des-methyl, des-amino pateamine A, a synthetic analogue of marine natural product pateamine A. Mol Cancer Ther 8 : 1250–1260.

41. HoffmannE, NeumannG, KawaokaY, HobomG, WebsterRG (2000) A DNA transfection system for generation of influenza A virus from eight plasmids. Proc Natl Acad Sci U S A 97 : 6108–6113.