1932

Abstract

Viral genomes harbor a variety of unusual translational phenomena that allow them to pack coding information more densely and evade host restriction mechanisms imposed by the cellular translational apparatus. Annotating translated sequences within these genomes thus poses particular challenges, but identifying the full complement of proteins encoded by a virus is critical for understanding its life cycle and defining the epitopes it presents for immune surveillance. Ribosome profiling is an emerging technique for global analysis of translation that offers direct and experimental annotation of viral genomes. Ribosome profiling has been applied to two herpesvirus genomes, those of human cytomegalovirus and Kaposi's sarcoma–associated herpesvirus, revealing translated sequences within presumptive long noncoding RNAs and identifying other micropeptides. Synthesis of these proteins has been confirmed by mass spectrometry and by identifying T cell responses following infection. Ribosome profiling in other viruses will likely expand further our understanding of viral gene regulation and the proteome.

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2015-11-09
2024-05-12
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Literature Cited

  1. Walsh D, Mathews MB, Mohr I. 1.  2013. Tinkering with translation: protein synthesis in virus-infected cells. Cold Spring Harb. Perspect. Biol. 5:a012351 [Google Scholar]
  2. Etchison D, Milburn SC, Edery I, Sonenberg N, Hershey JW. 2.  1982. Inhibition of HeLa cell protein synthesis following poliovirus infection correlates with the proteolysis of a 220,000-dalton polypeptide associated with eucaryotic initiation factor 3 and a cap binding protein complex. J. Biol. Chem. 257:14806–10 [Google Scholar]
  3. Kuyumcu-Martinez NM, Van Eden ME, Younan P, Lloyd RE. 3.  2004. Cleavage of poly(A)-binding protein by poliovirus 3C protease inhibits host cell translation: a novel mechanism for host translation shutoff. Mol. Cell. Biol. 24:1779–90 [Google Scholar]
  4. Kwong AD, Frenkel N. 4.  1987. Herpes simplex virus-infected cells contain a function(s) that destabilizes both host and viral mRNAs. PNAS 84:1926–30 [Google Scholar]
  5. Covarrubias S, Gaglia MM, Kumar GR, Wong W, Jackson AO, Glaunsinger BA. 5.  2011. Coordinated destruction of cellular messages in translation complexes by the gammaherpesvirus host shutoff factor and the mammalian exonuclease Xrn1. PLOS Pathog. 7:e1002339 [Google Scholar]
  6. Plotch SJ, Bouloy M, Ulmanen I, Krug RM. 6.  1981. A unique cap(m7GpppXm)-dependent influenza virion endonuclease cleaves capped RNAs to generate the primers that initiate viral RNA transcription. Cell 23:847–58 [Google Scholar]
  7. Firth AE, Brierley I. 7.  2012. Non-canonical translation in RNA viruses. J. Gen. Virol. 93:1385–409 [Google Scholar]
  8. Wise HM, Foeglein A, Sun J, Dalton RM, Patel S. 8.  et al. 2009. A complicated message: identification of a novel PB1-related protein translated from influenza A virus segment 2 mRNA. J. Virol. 83:8021–31 [Google Scholar]
  9. Wise HM, Barbezange C, Jagger BW, Dalton RM, Gog JR. 9.  et al. 2011. Overlapping signals for translational regulation and packaging of influenza A virus segment 2. Nucleic Acids Res. 39:7775–90 [Google Scholar]
  10. Wise HM, Hutchinson EC, Jagger BW, Stuart AD, Kang ZH. 10.  et al. 2012. Identification of a novel splice variant form of the influenza A virus M2 ion channel with an antigenically distinct ectodomain. PLOS Pathog. 8:e1002998 [Google Scholar]
  11. Muramoto Y, Noda T, Kawakami E, Akkina R, Kawaoka Y. 11.  2013. Identification of novel influenza A virus proteins translated from PA mRNA. J. Virol. 87:2455–62 [Google Scholar]
  12. Jagger BW, Wise HM, Kash JC, Walters KA, Wills NM. 12.  et al. 2012. An overlapping protein-coding region in influenza A virus segment 3 modulates the host response. Science 337:199–204 [Google Scholar]
  13. Ingolia NT, Ghaemmaghami S, Newman JRS, Weissman JS. 13.  2009. Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science 324:218–23 [Google Scholar]
  14. Ingolia NT. 14.  2014. Ribosome profiling: new views of translation, from single codons to genome scale. Nat. Rev. Genet. 15:205–13 [Google Scholar]
  15. Steitz JA. 15.  1969. Polypeptide chain initiation: nucleotide sequences of the three ribosomal binding sites in bacteriophage R17 RNA. Nature 224:957–64 [Google Scholar]
  16. Wolin SL, Walter P. 16.  1988. Ribosome pausing and stacking during translation of a eukaryotic mRNA. EMBO J. 7:3559–69 [Google Scholar]
  17. Guydosh NR, Green R. 17.  2014. Dom34 rescues ribosomes in 3′ untranslated regions. Cell 156:950–62 [Google Scholar]
  18. Ingolia NT, Lareau LF, Weissman JS. 18.  2011. Ribosome profiling of mouse embryonic stem cells reveals the complexity and dynamics of mammalian proteomes. Cell 147:789–802 [Google Scholar]
  19. Lareau LF, Hite DH, Hogan GJ, Brown PO. 19.  2014. Distinct stages of the translation elongation cycle revealed by sequencing ribosome-protected mRNA fragments. eLife 3:e01257 [Google Scholar]
  20. Chew GL, Pauli A, Rinn JL, Regev A, Schier AF, Valen E. 20.  2013. Ribosome profiling reveals resemblance between long non-coding RNAs and 5′ leaders of coding RNAs. Development 140:2828–34 [Google Scholar]
  21. Bazzini AA, Johnstone TG, Christiano R, MacKowiak SD, Obermayer B. 21.  et al. 2014. Identification of small ORFs in vertebrates using ribosome footprinting and evolutionary conservation. EMBO J. 33:981–93 [Google Scholar]
  22. Michel AM, Choudhury KR, Firth AE, Ingolia NT, Atkins JF, Baranov PV. 22.  2012. Observation of dually decoded regions of the human genome using ribosome profiling data. Genome Res. 22:2219–29 [Google Scholar]
  23. Brar GA, Yassour M, Friedman N, Regev A, Ingolia NT, Weissman JS. 23.  2012. High-resolution view of the yeast meiotic program revealed by ribosome profiling. Science 335:552–57 [Google Scholar]
  24. Stern-Ginossar N, Weisburd B, Michalski A, Le VTK, Hein MY. 24.  et al. 2012. Decoding human cytomegalovirus. Science 338:1088–93 [Google Scholar]
  25. Lee S, Liu B, Huang SX, Shen B, Qian SB. 25.  2012. Global mapping of translation initiation sites in mammalian cells at single-nucleotide resolution. PNAS 109:E2424–32 [Google Scholar]
  26. Fresno M, Jiménez A, Vázquez D. 26.  1977. Inhibition of translation in eukaryotic systems by harringtonine. Eur. J. Biochem. 72:323–30 [Google Scholar]
  27. Robert F, Carrier M, Rawe S, Chen S, Lowe S, Pelletier J. 27.  2009. Altering chemosensitivity by modulating translation elongation. PLOS ONE 4:e5428 [Google Scholar]
  28. Schneider-Poetsch T, Ju J, Eyler DE, Dang Y, Bhat S. 28.  et al. 2010. Inhibition of eukaryotic translation elongation by cycloheximide and lactimidomycin. Nat. Chem. Biol. 6:209–17 [Google Scholar]
  29. De Loubresse NG, Prokhorova I, Holtkamp W, Rodnina MV, Yusupova G, Yusupov M. 29.  2014. Structural basis for the inhibition of the eukaryotic ribosome. Nature 513:517–22 [Google Scholar]
  30. Fritsch C, Herrmann A, Nothnagel M, Szafranski K, Huse K. 30.  et al. 2012. Genome-wide search for novel human uORFs and N-terminal protein extensions using ribosomal footprinting. Genome Res. 22:2208–18 [Google Scholar]
  31. Gao X, Wan J, Liu B, Ma M, Shen B, Qian SB. 31.  2014. Quantitative profiling of initiating ribosomes in vivo. Nat. Methods 12:147–53 [Google Scholar]
  32. Calvo SE, Pagliarini DJ, Mootha VK. 32.  2009. Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans. PNAS 106:7507–12 [Google Scholar]
  33. Arribere JA, Gilbert WV. 33.  2013. Roles for transcript leaders in translation and mRNA decay revealed by transcript leader sequencing. Genome Res. 23:977–87 [Google Scholar]
  34. Pelechano V, Wei W, Jakob P, Steinmetz LM. 34.  2014. Genome-wide identification of transcript start and end sites by transcript isoform sequencing. Nat. Protoc. 9:1740–59 [Google Scholar]
  35. Sonenberg N, Hinnebusch AG. 35.  2009. Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136:731–45 [Google Scholar]
  36. Sadler AJ, Williams BRG. 36.  2008. Interferon-inducible antiviral effectors. Nat. Rev. Immunol. 8:559–68 [Google Scholar]
  37. Elde NC, Child SJ, Eickbush MT, Kitzman JO, Rogers KS. 37.  et al. 2012. Poxviruses deploy genomic accordions to adapt rapidly against host antiviral defenses. Cell 150:831–41 [Google Scholar]
  38. Rothenburg S, Seo EJ, Gibbs JS, Dever TE, Dittmar K. 38.  2009. Rapid evolution of protein kinase PKR alters sensitivity to viral inhibitors. Nat. Struct. Mol. Biol. 16:63–70 [Google Scholar]
  39. Andreev DE, O'Connor PB, Fahey C, Kenny EM, Terenin IM. 39.  et al. 2015. Translation of 5′ leaders is pervasive in genes resistant to eIF2 repression. eLife 4:e03971 [Google Scholar]
  40. Sidrauski C, McGeachy AM, Ingolia NT, Walter P. 40.  2015. The small molecule ISRIB reverses the effects of eIF2α phosphorylation on translation and stress granule assembly. eLife 4:e05033 [Google Scholar]
  41. Touriol C, Bornes S, Bonnal S, Audigier S, Prats H. 41.  et al. 2003. Generation of protein isoform diversity by alternative initiation of translation at non-AUG codons. Biol. Cell 95:169–78 [Google Scholar]
  42. Ivanov IP, Firth AE, Michel AM, Atkins JF, Baranov PV. 42.  2011. Identification of evolutionarily conserved non-AUG-initiated N-terminal extensions in human coding sequences. Nucleic Acids Res. 39:4220–34 [Google Scholar]
  43. Hopkins BD, Fine B, Steinbach N, Dendy M, Rapp Z. 43.  et al. 2013. A secreted PTEN phosphatase that enters cells to alter signaling and survival. Science 341:399–402 [Google Scholar]
  44. Menschaert G, Van Criekinge W, Notelaers T, Koch A, Crappé J. 44.  et al. 2013. Deep proteome coverage based on ribosome profiling aids mass spectrometry-based protein and peptide discovery and provides evidence of alternative translation products and near-cognate translation initiation events. Mol. Cell. Proteomics 12:1780–90 [Google Scholar]
  45. Van Damme P, Gawron D, Van Criekinge W, Menschaert G. 45.  2014. N-terminal proteomics and ribosome profiling provide a comprehensive view of the alternative translation initiation landscape in mice and men. Mol. Cell. Proteomics 13:1245–61 [Google Scholar]
  46. Fournier CT, Cherny JJ, Truncali K, Robbins-Pianka A, Lin MS. 46.  et al. 2012. Amino termini of many yeast proteins map to downstream start codons. J. Proteome Res. 11:5712–19 [Google Scholar]
  47. Brubaker SW, Gauthier AE, Mills EW, Ingolia NT, Kagan JC. 47.  2014. A bicistronic MAVS transcript highlights a class of truncated variants in antiviral immunity. Cell 156:800–11 [Google Scholar]
  48. Calkhoven CF, Muller C, Leutz A. 48.  2000. Translational control of C/EBPα and C/EBPβ isoform expression. Genes Dev. 14:1920–32 [Google Scholar]
  49. Lord PC, Rothschild CB, DeRose RT, Kilpatrick BA. 49.  1989. Human cytomegalovirus RNAs immunoprecipitated by multiple systemic lupus erythematosus antisera. J. Gen. Virol. 70:2383–96 [Google Scholar]
  50. Van Heesch S, van Iterson M, Jacobi J, Boymans S, Essers PB. 50.  et al. 2014. Extensive localization of long noncoding RNAs to the cytosol and mono- and polyribosomal complexes. Genome Biol. 15R6
  51. Zhou P, Zhang Y, Ma Q, Gu F, Day DS. 51.  et al. 2013. Interrogating translational efficiency and lineage-specific transcriptomes using ribosome affinity purification. PNAS 110:15395–400 [Google Scholar]
  52. Ingolia NT, Brar GA, Stern-Ginossar N, Harris MS, Talhouarne GJS. 52.  et al. 2014. Ribosome profiling reveals pervasive translation outside of annotated protein-coding genes. Cell Rep. 8:1365–79 [Google Scholar]
  53. Ulitsky I, Bartel DP. 53.  2013. lincRNSs: genomics, evolution, and mechanisms. Cell 154:26–46 [Google Scholar]
  54. Ulitsky I, Shkumatava A, Jan CH, Sive H, Bartel DP. 54.  2011. Conserved function of lincRNAs in vertebrate embryonic development despite rapid sequence evolution. Cell 147:1537–50 [Google Scholar]
  55. Kloc M, Wilk K, Vargas D, Shirato Y, Bilinski S, Etkin LD. 55.  2005. Potential structural role of non-coding and coding RNAs in the organization of the cytoskeleton at the vegetal cortex of Xenopus oocytes. Development 132:3445–57 [Google Scholar]
  56. Smith CM, Steitz JA. 56.  1998. Classification of gas5 as a multi-small-nucleolar-RNA (snoRNA) host gene and a member of the 5′-terminal oligopyrimidine gene family reveals common features of snoRNA host genes. Mol. Cell. Biol. 18:6897–909 [Google Scholar]
  57. Barker GF, Beemon K. 57.  1994. Rous sarcoma virus RNA stability requires an open reading frame in the gag gene and sequences downstream of the gag-pol junction. Mol. Cell. Biol. 14:1986–96 [Google Scholar]
  58. LeBlanc JJ, Beemon KL. 58.  2004. Unspliced Rous sarcoma virus genomic RNAs are translated and subjected to nonsense-mediated mRNA decay before packaging. J. Virol. 78:5139–46 [Google Scholar]
  59. Kondo T, Plaza S, Zanet J, Benrabah E, Valenti P. 59.  et al. 2010. Small peptides switch the transcriptional activity of Shavenbaby during Drosophila embryogenesis. Science 329:336–39 [Google Scholar]
  60. Magny EG, Pueyo JI, Pearl FMG, Cespedes MA, Niven JE. 60.  et al. 2013. Conserved regulation of cardiac calcium uptake by peptides encoded in small open reading frames. Science 341:1116–20 [Google Scholar]
  61. Pauli A, Norris ML, Valen E, Chew GL, Gagnon JA. 61.  et al. 2014. Toddler: an embryonic signal that promotes cell movement via Apelin receptors. Science 343:1248636 [Google Scholar]
  62. Anderson DM, Anderson KM, Chang CL, Makarewich CA, Nelson BR. 62.  et al. 2015. A micropeptide encoded by a putative long noncoding RNA regulates muscle performance. Cell 160:595–606 [Google Scholar]
  63. Crappé J, Van Criekinge W, Trooskens G, Hayakawa E, Luyten W. 63.  et al. 2013. Combining in silico prediction and ribosome profiling in a genome-wide search for novel putatively coding sORFs. BMC Genomics 14:648 [Google Scholar]
  64. Lin MF, Jungreis I, Kellis M. 64.  2011. PhyloCSF: a comparative genomics method to distinguish protein coding and non-coding regions. Bioinformatics 27:i275–82 [Google Scholar]
  65. Slavoff SA, Mitchell AJ, Schwaid AG, Cabili MN, Ma J. 65.  et al. 2013. Peptidomic discovery of short open reading frame-encoded peptides in human cells. Nat. Chem. Biol. 9:59–64 [Google Scholar]
  66. Smith JE, Alvarez-Dominguez JR, Kline N, Huynh NJ, Geisler S. 66.  et al. 2014. Translation of small open reading frames within unannotated RNA transcripts in Saccharomyces cerevisiae. Cell Rep. 7:1858–66 [Google Scholar]
  67. Aspden JL, Eyre-Walker YC, Phillips RJ, Amin U, Mumtaz MAS. 67.  et al. 2014. Extensive translation of small open reading frames revealed by Poly-Ribo-Seq. eLife 3:e03528 [Google Scholar]
  68. Davison AJ, Dolan A, Akter P, Addison C, Dargan DJ. 68.  et al. 2003. The human cytomegalovirus genome revisited: comparison with the chimpanzee cytomegalovirus genome. J. Gen. Virol. 84:17–28 [Google Scholar]
  69. Murphy E, Rigoutsos I, Shibuya T, Shenk TE. 69.  2003. Reevaluation of human cytomegalovirus coding potential. PNAS 100:13585–90 [Google Scholar]
  70. Reeves MB, Davies AA, McSharry BP, Wilkinson GW, Sinclair JH. 70.  2007. Complex I binding by a virally encoded RNA regulates mitochondria-induced cell death. Science 316:1345–48 [Google Scholar]
  71. Yewdell JW. 71.  2007. Plumbing the sources of endogenous MHC class I peptide ligands. Curr. Opin. Immunol. 19:79–86 [Google Scholar]
  72. Sylwester AW, Mitchell BL, Edgar JB, Taormina C, Pelte C. 72.  et al. 2005. Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J. Exp. Med. 202:673–85 [Google Scholar]
  73. Russo JJ, Bohenzky RA, Chien MC, Chen J, Yan M. 73.  et al. 1996. Nucleotide sequence of the Kaposi sarcoma-associated herpesvirus (HHV8). PNAS 93:14862–67 [Google Scholar]
  74. Arias C, Weisburd B, Stern-Ginossar N, Mercier A, Madrid AS. 74.  et al. 2014. KSHV 2.0: a comprehensive annotation of the Kaposi's sarcoma-associated herpesvirus genome using next-generation sequencing reveals novel genomic and functional features. PLOS Pathog. 10:e1003847 [Google Scholar]
  75. Sun R, Lin SF, Gradoville L, Miller G. 75.  1996. Polyadenylylated nuclear RNA encoded by Kaposi sarcoma-associated herpesvirus. PNAS 93:11883–88 [Google Scholar]
  76. Reid DW, Nicchitta CV. 76.  2012. The enduring enigma of nuclear translation. J. Cell Biol. 197:7–9 [Google Scholar]
  77. Kronstad LM, Brulois KF, Jung JU, Glaunsinger BA. 77.  2013. Dual short upstream open reading frames control translation of a herpesviral polycistronic mRNA. PLOS Pathog. 9:e1003156 [Google Scholar]
  78. Fields BN, Knipe DM. 78.  1990. Fields Virology New York: Raven, 2nd ed..
  79. Yang Z, Cao S, Martens CA, Porcella SF, Xie Z. 79.  et al. 2015. Deciphering poxvirus gene expression by RNA sequencing and ribosome profiling. J. Virol. 89:6874–86 [Google Scholar]
  80. Yang Z, Martens CA, Bruno DP, Porcella SF, Moss B. 80.  2012. Pervasive initiation and 3′-end formation of poxvirus postreplicative RNAs. J. Biol. Chem. 287:31050–60 [Google Scholar]
  81. Roberts JW, Yarnell W, Bartlett E, Guo J, Marr M. 82.  et al. 1998. Antitermination by bacteriophage Q protein. Cold Spring Harb. Symp. Quant. Biol. 63:319–26 [Google Scholar]
  82. Liu X, Jiang H, Gu Z, Roberts JW. 81.  2013. High-resolution view of bacteriophage lambda gene expression by ribosome profiling. PNAS 110:11928–33 [Google Scholar]
  83. Xu J, Hendrix RW, Duda RL. 83.  2004. Conserved translational frameshift in dsDNA bacteriophage tail assembly genes. Mol. Cell 16:11–21 [Google Scholar]
  84. Dunn JG, Foo CK, Belletier NG, Gavis ER, Weissman JS. 84.  2013. Ribosome profiling reveals pervasive and regulated stop codon readthrough in Drosophila melanogaster. eLife 2e01179
  85. Weekes MP, Tomasec P, Huttlin EL, Fielding CA, Nusinow D. 85.  et al. 2014. Quantitative temporal viromics: an approach to investigate host-pathogen interaction. Cell 157:1460–72 [Google Scholar]
  86. Sanger F, Nicklen S, Coulson AR. 86.  1977. DNA sequencing with chain-terminating inhibitors. PNAS 74:5463–67 [Google Scholar]
  87. Fiers W, Contreras R, Haegemann G, Rogiers R, Van de Voorde A. 87.  et al. 1978. Complete nucleotide sequence of SV40 DNA. Nature 273:113–20 [Google Scholar]
  88. Reddy VB, Thimmappaya B, Dhar R, Subramanian KN, Zain BS. 88.  et al. 1978. The genome of simian virus 40. Science 200:494–502 [Google Scholar]
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