IRES Elements: Issues, Controversies and Evolutionary Perspectives

  • Rosario Francisco-Velilla
  • Gloria Lozano
  • Rosa Diaz-Toledano
  • Javier Fernandez-Chamorro
  • Azman M. Embarek
  • Encarnacion Martinez-SalasEmail author


Internal ribosome entry site (IRES) elements are cis-acting RNA regions that have the capacity to recruit the translation machinery internally using a cap-independent mechanism. Distinct types of IRES elements present in the genome of various RNA viruses, and in a subset of cellular mRNAs, perform the same function despite lacking conservation of primary sequence and secondary RNA structure. Likewise, they also differ in the host factor requirement to recruit the ribosomal subunits. In spite of this diversity, evolutionarily conserved motifs preserve sequences impacting on RNA structure and RNA-protein interactions important for each type of IRES element. Notwithstanding the lack of a universal RNA motif unique to all IRES elements, understanding of the structural motifs important for IRES function could greatly improve the accuracy to predict IRES-like motifs hidden in genome sequences and, moreover, to decipher the evolutionary history of these regulatory elements. Here we discuss the evolutionary perspectives of IRES elements based on the diversity of cap-independent translation mechanisms and on the RNA structure features of currently known IRES elements contributing to their activity.


IRES elements Evolutionary origin Conserved motifs RNA structure Ribosome interaction Transacting factors 



This work was supported by grant BFU2014-54564-P from MINECO and by an Institutional grant from Fundación Ramón Areces.


  1. 1.
    Sonenberg N, Hinnebusch AG. Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell. 2009;136(4):731–45.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Pelletier J, Sonenberg N. Internal initiation of translation of eukaryotic mRNA directed by a sequence derived from poliovirus RNA. Nature. 1988;334(6180):320–5.CrossRefPubMedGoogle Scholar
  3. 3.
    Jang SK, Krausslich HG, Nicklin MJ, Duke GM, Palmenberg AC, 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;62(8):2636–43.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Meyer KD, Patil DP, Zhou J, Zinoviev A, Skabkin MA, Elemento O, et al. 5′ UTR m(6)A promotes cap-independent translation. Cell. 2015;163(4):999–1010.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Zhou J, Wan J, Gao X, Zhang X, Jaffrey SR, Qian SB. Dynamic m(6)A mRNA methylation directs translational control of heat shock response. Nature. 2015;526(7574):591–4.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Paek KY, Hong KY, Ryu I, Park SM, Keum SJ, Kwon OS, et al. Translation initiation mediated by RNA looping. Proc Natl Acad Sci USA. 2015;112(4):1041–6.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Walsh D, Mohr I. Viral subversion of the host protein synthesis machinery. Nat Rev Microbiol. 2011;9(12):860–75.CrossRefPubMedGoogle Scholar
  8. 8.
    Honda M, Ping LH, Rijnbrand RC, Amphlett E, Clarke B, Rowlands D, et al. Structural requirements for initiation of translation by internal ribosome entry within genome-length hepatitis C virus RNA. Virology. 1996;222(1):31–42.CrossRefPubMedGoogle Scholar
  9. 9.
    Wilson JE, Pestova TV, Hellen CU, Sarnow P. Initiation of protein synthesis from the A site of the ribosome. Cell. 2000;102(4):511–20.CrossRefPubMedGoogle Scholar
  10. 10.
    Vallejos M, Deforges J, Plank TD, Letelier A, Ramdohr P, Abraham CG, et al. Activity of the human immunodeficiency virus type 1 cell cycle-dependent internal ribosomal entry site is modulated by IRES trans-acting factors. Nucleic Acids Res. 2011;39(14):6186–200.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Herbreteau CH, Weill L, Decimo D, Prevot D, Darlix JL, Sargueil B, et al. HIV-2 genomic RNA contains a novel type of IRES located downstream of its initiation codon. Nat Struct Mol Biol. 2005;12(11):1001–7.CrossRefPubMedGoogle Scholar
  12. 12.
    Xue S, Tian S, Fujii K, Kladwang W, Das R, Barna M. RNA regulons in Hox 5′ UTRs confer ribosome specificity to gene regulation. Nature. 2015;517(7532):33–8.CrossRefPubMedGoogle Scholar
  13. 13.
    Du X, Wang J, Zhu H, Rinaldo L, Lamar KM, Palmenberg AC, et al. Second cistron in CACNA1A gene encodes a transcription factor mediating cerebellar development and SCA6. Cell. 2013;154(1):118–33.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Burkart C, Fan JB, Zhang DE. Two independent mechanisms promote expression of an N-terminal truncated USP18 isoform with higher DeISGylation activity in the nucleus. J Biol Chem. 2012;287(7):4883–93.CrossRefPubMedGoogle Scholar
  15. 15.
    Henis-Korenblit S, Shani G, Sines T, Marash L, Shohat G, Kimchi A. The caspase-cleaved DAP5 protein supports internal ribosome entry site-mediated translation of death proteins. Proc Natl Acad Sci USA. 2002;99(8):5400–5.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Ul-Hussain M, Olk S, Schoenebeck B, Wasielewski B, Meier C, Prochnow N, et al. Internal ribosomal entry site (IRES) activity generates endogenous carboxyl-terminal domains of Cx43 and is responsive to hypoxic conditions. J Biol Chem. 2014;289(30):20979–90.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Sasaki J, Nakashima N. Translation initiation at the CUU codon is mediated by the internal ribosome entry site of an insect picorna-like virus in vitro. J Virol. 1999;73(2):1219–26.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Nakashima N, Uchiumi T. Functional analysis of structural motifs in dicistroviruses. Virus Res. 2009;139(2):137–47.CrossRefPubMedGoogle Scholar
  19. 19.
    Fernandez N, Fernandez-Miragall O, Ramajo J, Garcia-Sacristan A, Bellora N, Eyras E, et al. Structural basis for the biological relevance of the invariant apical stem in IRES-mediated translation. Nucleic Acids Res. 2011;39(19):8572–85.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Fernandez N, Buddrus L, Pineiro D, Martinez-Salas E. Evolutionary conserved motifs constrain the RNA structure organization of picornavirus IRES. FEBS Lett. 2013;587(9):1353–8.CrossRefPubMedGoogle Scholar
  21. 21.
    Au HH, Cornilescu G, Mouzakis KD, Ren Q, Burke JE, Lee S, et al. Global shape mimicry of tRNA within a viral internal ribosome entry site mediates translational reading frame selection. Proc Natl Acad Sci USA. 2015;112(47):E6446–55.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Fernandez IS, Bai XC, Murshudov G, Scheres SH, Ramakrishnan V. Initiation of translation by cricket paralysis virus IRES requires its translocation in the ribosome. Cell. 2014;157(4):823–31.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Martinez-Salas E, Francisco-Velilla R, Fernandez-Chamorro J, Lozano G, Diaz-Toledano R. Picornavirus IRES elements: RNA structure and host protein interactions. Virus Res. 2015;206:62–73.CrossRefPubMedGoogle Scholar
  24. 24.
    Pestova TV, Shatsky IN, Fletcher SP, Jackson RJ, Hellen CU. A prokaryotic-like mode of cytoplasmic eukaryotic ribosome binding to the initiation codon during internal translation initiation of hepatitis C and classical swine fever virus RNAs. Genes Dev. 1998;12(1):67–83.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Filbin ME, Vollmar BS, Shi D, Gonen T, Kieft JS. HCV IRES manipulates the ribosome to promote the switch from translation initiation to elongation. Nat Struct Mol Biol. 2013;20(2):150–8.CrossRefPubMedGoogle Scholar
  26. 26.
    Kieft JS, Zhou K, Jubin R, Doudna JA. Mechanism of ribosome recruitment by hepatitis C IRES RNA. RNA. 2001;7(2):194–206.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Perard J, Leyrat C, Baudin F, Drouet E, Jamin M. Structure of the full-length HCV IRES in solution. Nat Commun. 2013;4:1612.CrossRefPubMedGoogle Scholar
  28. 28.
    Yamamoto H, Collier M, Loerke J, Ismer J, Schmidt A, Hilal T, et al. Molecular architecture of the ribosome-bound Hepatitis C Virus internal ribosomal entry site RNA. EMBO J. 2015;34(24):3042–58.CrossRefPubMedGoogle Scholar
  29. 29.
    Garcia-Sacristan A, Moreno M, Ariza-Mateos A, Lopez-Camacho E, Jaudenes RM, Vazquez L, et al. A magnesium-induced RNA conformational switch at the internal ribosome entry site of hepatitis C virus genome visualized by atomic force microscopy. Nucleic Acids Res. 2015;43(1):565–80.CrossRefPubMedGoogle Scholar
  30. 30.
    Hashem Y, des Georges A, Dhote V, Langlois R, Liao HY, Grassucci RA, et al. Hepatitis-C-virus-like internal ribosome entry sites displace eIF3 to gain access to the 40S subunit. Nature. 2013;503(7477):539–43.Google Scholar
  31. 31.
    Asnani M, Kumar P, Hellen CU. Widespread distribution and structural diversity of Type IV IRESs in members of Picornaviridae. Virology. 2015;478:61–74.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Bailey JM, Tapprich WE. Structure of the 5′ nontranslated region of the coxsackievirus b3 genome: chemical modification and comparative sequence analysis. J Virol. 2007;81(2):650–68.CrossRefPubMedGoogle Scholar
  33. 33.
    Yu Y, Sweeney TR, Kafasla P, Jackson RJ, Pestova TV, Hellen CU. The mechanism of translation initiation on Aichivirus RNA mediated by a novel type of picornavirus IRES. EMBO J. 2011;30(21):4423–36.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Kolupaeva VG, Pestova TV, Hellen CU, Shatsky IN. Translation eukaryotic initiation factor 4G recognizes a specific structural element within the internal ribosome entry site of encephalomyocarditis virus RNA. J Biol Chem. 1998;273(29):18599–604.CrossRefPubMedGoogle Scholar
  35. 35.
    de Breyne S, Yu Y, Unbehaun A, Pestova TV, Hellen CU. Direct functional interaction of initiation factor eIF4G with type 1 internal ribosomal entry sites. Proc Natl Acad Sci USA. 2009;106(23):9197–202.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Ali IK, McKendrick L, Morley SJ, Jackson RJ. Activity of the hepatitis A virus IRES requires association between the cap-binding translation initiation factor (eIF4E) and eIF4G. J Virol. 2001;75(17):7854–63.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Pisarev AV, Chard LS, Kaku Y, Johns HL, Shatsky IN, Belsham GJ. Functional and structural similarities between the internal ribosome entry sites of hepatitis C virus and porcine teschovirus, a picornavirus. J Virol. 2004;78(9):4487–97.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Olarte-Castillo XA, Heeger F, Mazzoni CJ, Greenwood AD, Fyumagwa R, Moehlman PD, et al. Molecular characterization of canine kobuvirus in wild carnivores and the domestic dog in Africa. Virology. 2015;477:89–97.CrossRefPubMedGoogle Scholar
  39. 39.
    Lau SK, Woo PC, Lai KK, Huang Y, Yip CC, Shek CT, et al. Complete genome analysis of three novel picornaviruses from diverse bat species. J Virol. 2011;85(17):8819–28.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Hellen CU, de Breyne S. A distinct group of hepacivirus/pestivirus-like internal ribosomal entry sites in members of diverse picornavirus genera: evidence for modular exchange of functional noncoding RNA elements by recombination. J Virol. 2007;81(11):5850–63.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Lozano G, Trapote A, Ramajo J, Elduque X, Grandas A, Robles J, et al. Local RNA flexibility perturbation of the IRES element induced by a novel ligand inhibits viral RNA translation. RNA Biol. 2015;12(5):555–68.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Boerneke MA, Dibrov SM, Gu J, Wyles DL, Hermann T. Functional conservation despite structural divergence in ligand-responsive RNA switches. Proc Natl Acad Sci USA. 2014;111(45):15952–7.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Laxton C, Brady K, Moschos S, Turnpenny P, Rawal J, Pryde DC, et al. Selection, optimization, and pharmacokinetic properties of a novel, potent antiviral locked nucleic acid-based antisense oligomer targeting hepatitis C virus internal ribosome entry site. Antimicrob Agents Chemother. 2011;55(7):3105–14.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Stone JK, Rijnbrand R, Stein DA, Ma Y, Yang Y, Iversen PL, et al. A morpholino oligomer targeting highly conserved internal ribosome entry site sequence is able to inhibit multiple species of picornavirus. Antimicrob Agents Chemother. 2008;52(6):1970–81.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Fajardo T Jr, Rosas MF, Sobrino F, Martinez-Salas E. Exploring IRES Region Accessibility by Interference of Foot-and-Mouth Disease Virus Infectivity. PLoS ONE. 2012;7(7):e41382.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Soto-Rifo R, Rubilar PS, Limousin T, de Breyne S, Decimo D, Ohlmann T. DEAD-box protein DDX3 associates with eIF4F to promote translation of selected mRNAs. EMBO J. 2012;31(18):3745–56.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Locker N, Chamond N, Sargueil B. A conserved structure within the HIV gag open reading frame that controls translation initiation directly recruits the 40S subunit and eIF3. Nucleic Acids Res. 2011;39(6):2367–77.CrossRefPubMedGoogle Scholar
  48. 48.
    Dorokhov YL, Ivanov PA, Komarova TV, Skulachev MV, Atabekov JG. An internal ribosome entry site located upstream of the crucifer-infecting tobamovirus coat protein (CP) gene can be used for CP synthesis in vivo. J Gen Virol. 2006;87(Pt 9):2693–7.CrossRefPubMedGoogle Scholar
  49. 49.
    Groppelli E, Belsham GJ, Roberts LO. Identification of minimal sequences of the Rhopalosiphum padi virus 5′ untranslated region required for internal initiation of protein synthesis in mammalian, plant and insect translation systems. J Gen Virol. 2007;88(Pt 5):1583–8.CrossRefPubMedGoogle Scholar
  50. 50.
    Abaeva IS, Pestova TV, Hellen CU. Attachment of ribosomal complexes and retrograde scanning during initiation on the Halastavi arva virus IRES. Nucleic Acids Res. 2016;44(5):2362–77.Google Scholar
  51. 51.
    Le Quesne JP, Stoneley M, Fraser GA, Willis AE. Derivation of a structural model for the c-myc IRES. J Mol Biol. 2001;310(1):111–26.CrossRefPubMedGoogle Scholar
  52. 52.
    Baird SD, Lewis SM, Turcotte M, Holcik M. A search for structurally similar cellular internal ribosome entry sites. Nucleic Acids Res. 2007;35(14):4664–77.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Jimenez-Gonzalez AS, Fernandez N, Martinez-Salas E. Sanchez de Jimenez E. Functional and structural analysis of maize hsp101 IRES. PLoS ONE. 2014;9(9):e107459.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Bisio A, Latorre E, Andreotti V, Bressac-de Paillerets B, Harland M, Scarra GB, et al. The 5′-untranslated region of p16INK4a melanoma tumor suppressor acts as a cellular IRES, controlling mRNA translation under hypoxia through YBX1 binding. Oncotarget. 2015;6(37):39980–94.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Spahn CM, Jan E, Mulder A, Grassucci RA, Sarnow P, Frank J. Cryo-EM visualization of a viral internal ribosome entry site bound to human ribosomes: the IRES functions as an RNA-based translation factor. Cell. 2004;118(4):465–75.CrossRefPubMedGoogle Scholar
  56. 56.
    Matsuda D, Mauro VP. Base pairing between hepatitis C virus RNA and 18S rRNA is required for IRES-dependent translation initiation in vivo. Proc Natl Acad Sci USA. 2014;111(43):15385–9.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Chappell SA, Edelman GM, Mauro VP. A 9-nt segment of a cellular mRNA can function as an internal ribosome entry site (IRES) and when present in linked multiple copies greatly enhances IRES activity. Proc Natl Acad Sci USA. 2000;97(4):1536–41.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Bhattacharyya D, Diamond P, Basu S. An Independently folding RNA G-quadruplex domain directly recruits the 40S ribosomal subunit. Biochemistry. 2015;54(10):1879–85.CrossRefPubMedGoogle Scholar
  59. 59.
    Malygin AA, Kossinova OA, Shatsky IN, Karpova GG. HCV IRES interacts with the 18S rRNA to activate the 40S ribosome for subsequent steps of translation initiation. Nucleic Acids Res. 2013;41(18):8706–14.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Angulo J, Ulryck N, Deforges J, Chamond N, Lopez-Lastra M, Masquida B, et al. LOOP IIId of the HCV IRES is essential for the structural rearrangement of the 40S-HCV IRES complex. Nucleic Acids Res. 2016;44(3):1309–25.Google Scholar
  61. 61.
    Weingarten-Gabbay S, Elias-Kirma S, Nir R, Gritsenko AA, Stern-Ginossar N, Yakhini Z, et al. Comparative genetics. Systematic discovery of cap-independent translation sequences in human and viral genomes. Science. 2016;351(6270).Google Scholar
  62. 62.
    Sean P, Nguyen JH, Semler BL. Altered interactions between stem-loop IV within the 5′ noncoding region of coxsackievirus RNA and poly(rC) binding protein 2: effects on IRES-mediated translation and viral infectivity. Virology. 2009;389(1–2):45–58.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Fernandez N, Garcia-Sacristan A, Ramajo J, Briones C, Martinez-Salas E. Structural analysis provides insights into the modular organization of picornavirus IRES. Virology. 2011;409(2):251–61.CrossRefPubMedGoogle Scholar
  64. 64.
    Kaminski A, Belsham GJ, Jackson RJ. Translation of encephalomyocarditis virus RNA: parameters influencing the selection of the internal initiation site. EMBO J. 1994;13(7):1673–81.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Jang SK, Wimmer E. Cap-independent translation of encephalomyocarditis virus RNA: structural elements of the internal ribosomal entry site and involvement of a cellular 57-kD RNA-binding protein. Genes Dev. 1990;4:1560–72.CrossRefPubMedGoogle Scholar
  66. 66.
    Fernandez-Miragall O, Martinez-Salas E. Structural organization of a viral IRES depends on the integrity of the GNRA motif. RNA. 2003;9(11):1333–44.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Lozano G, Fernandez N, Martinez-Salas E. Magnesium-dependent folding of a picornavirus IRES element modulates RNA conformation and eIF4G interaction. FEBS J. 2014;281(16):3685–700.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    de Quinto Lopez. S, Martinez-Salas E. Interaction of the eIF4G initiation factor with the aphthovirus IRES is essential for internal translation initiation in vivo. RNA. 2000;6(10):1380–92.CrossRefGoogle Scholar
  69. 69.
    Clark AT, Robertson ME, Conn GL, Belsham GJ. Conserved nucleotides within the J domain of the encephalomyocarditis virus internal ribosome entry site are required for activity and for interaction with eIF4G. J Virol. 2003;77(23):12441–9.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    de Quinto Lopez. S, Lafuente E, Martinez-Salas E. IRES interaction with translation initiation factors: functional characterization of novel RNA contacts with eIF3, eIF4B, and eIF4GII. RNA. 2001;7(9):1213–26.CrossRefGoogle Scholar
  71. 71.
    Fernandez-Chamorro J, Pineiro D, Gordon JM, Ramajo J, Francisco-Velilla R, Macias MJ, et al. Identification of novel non-canonical RNA-binding sites in Gemin5 involved in internal initiation of translation. Nucleic Acids Res. 2014;42(9):5742–54.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Ochs K, Rust RC, Niepmann M. Translation initiation factor eIF4B interacts with a picornavirus internal ribosome entry site in both 48S and 80S initiation complexes independently of initiator AUG location. J Virol. 1999;73(9):7505–14.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Pineiro D, Fernandez N, Ramajo J, Martinez-Salas E. Gemin5 promotes IRES interaction and translation control through its C-terminal region. Nucleic Acids Res. 2013;41(2):1017–28.CrossRefPubMedGoogle Scholar
  74. 74.
    Fernandez-Miragall O, Lopez de Quinto S, Martinez-Salas E. Relevance of RNA structure for the activity of picornavirus IRES elements. Virus Res. 2009;139(2):172–82.Google Scholar
  75. 75.
    Serrano P, Ramajo J, Martinez-Salas E. Rescue of internal initiation of translation by RNA complementation provides evidence for a distribution of functions between individual IRES domains. Virology. 2009;388(1):221–9.CrossRefPubMedGoogle Scholar
  76. 76.
    Roberts LO, Belsham GJ. Complementation of defective picornavirus internal ribosome entry site (IRES) elements by the coexpression of fragments of the IRES. Virology. 1997;227(1):53–62.CrossRefPubMedGoogle Scholar
  77. 77.
    Andreev DE, Fernandez-Miragall O, Ramajo J, Dmitriev SE, Terenin IM, Martinez-Salas E, et al. Differential factor requirement to assemble translation initiation complexes at the alternative start codons of foot-and-mouth disease virus RNA. RNA. 2007;13(8):1366–74.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Sweeney TR, Abaeva IS, Pestova TV, Hellen CU. The mechanism of translation initiation on Type 1 picornavirus IRESs. EMBO J. 2014;33(1):76–92.CrossRefPubMedGoogle Scholar
  79. 79.
    Yu Y, Abaeva IS, Marintchev A, Pestova TV, Hellen CU. Common conformational changes induced in type 2 picornavirus IRESs by cognate trans-acting factors. Nucleic Acids Res. 2011;39(11):4851–65.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Kafasla P, Morgner N, Poyry TA, Curry S, Robinson CV, Jackson RJ. Polypyrimidine tract binding protein stabilizes the encephalomyocarditis virus IRES structure via binding multiple sites in a unique orientation. Mol Cell. 2009;34(5):556–68.CrossRefPubMedGoogle Scholar
  81. 81.
    Spriggs KA, Cobbold LC, Jopling CL, Cooper RE, Wilson LA, Stoneley M, et al. Canonical initiation factor requirements of the Myc family of internal ribosome entry segments. Mol Cell Biol. 2009;29(6):1565–74.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Majumder M, Yaman I, Gaccioli F, Zeenko VV, Wang C, Caprara MG, et al. The hnRNA-binding proteins hnRNP L and PTB are required for efficient translation of the Cat-1 arginine/lysine transporter mRNA during amino acid starvation. Mol Cell Biol. 2009;29(10):2899–912.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Mitchell SA, Spriggs KA, Bushell M, Evans JR, Stoneley M, Le Quesne JP, et al. Identification of a motif that mediates polypyrimidine tract-binding protein-dependent internal ribosome entry. Genes Dev. 2005;19:1556–71.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Mitchell SA, Spriggs KA, Coldwell MJ, Jackson RJ, Willis AE. The Apaf-1 internal ribosome entry segment attains the correct structural conformation for function via interactions with PTB and unr. Mol Cell. 2003;11(3):757–71.CrossRefPubMedGoogle Scholar
  85. 85.
    Yang B, Hu P, Lin X, Han W, Zhu L, Tan X, et al. PTBP1 induces ADAR1 p110 isoform expression through IRES-like dependent translation control and influences cell proliferation in gliomas. Cell Mol Life Sci. 2015;72(22):4383–97.CrossRefPubMedGoogle Scholar
  86. 86.
    Ungureanu NH, Cloutier M, Lewis SM, de Silva N, Blais JD, Bell JC, et al. Internal ribosome entry site-mediated translation of Apaf-1, but not XIAP, is regulated during UV-induced cell death. J Biol Chem. 2006;281(22):15155–63.CrossRefPubMedGoogle Scholar
  87. 87.
    de Quinto Lopez. S, Saiz M, de la Morena D, Sobrino F, Martinez-Salas E. IRES-driven translation is stimulated separately by the FMDV 3′-NCR and poly(A) sequences. Nucleic Acids Res. 2002;30(20):4398–405.CrossRefGoogle Scholar
  88. 88.
    Song Y, Friebe P, Tzima E, Junemann C, Bartenschlager R, Niepmann M. The hepatitis C virus RNA 3′-untranslated region strongly enhances translation directed by the internal ribosome entry site. J Virol. 2006;80(23):11579–88.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Bradrick SS, Dobrikova EY, Kaiser C, Shveygert M, Gromeier M. Poly(A)-binding protein is differentially required for translation mediated by viral internal ribosome entry sites. RNA. 2007;13(9):1582–93.CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Marom L, Hen-Avivi S, Pinchasi D, Chekanova JA, Belostotsky DA, Elroy-Stein O. Diverse poly(A) binding proteins mediate internal translational initiation by a plant viral IRES. RNA Biol. 2009;6(4):446–54.CrossRefPubMedGoogle Scholar
  91. 91.
    Martinez-Salas E, Pineiro D, Fernandez N. Alternative Mechanisms to Initiate Translation in Eukaryotic mRNAs. Comp Funct Genomics. 2012;2012:391546.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Meng Z, Jackson NL, Shcherbakov OD, Choi H, Blume SW. The human IGF1R IRES likely operates through a Shine-Dalgarno-like interaction with the G961 loop (E-site) of the 18S rRNA and is kinetically modulated by a naturally polymorphic polyU loop. J Cell Biochem. 2010;110(2):531–44.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Peredo EL, Les DH, King UM, Benoit LK. Extreme conservation of the psaA/psaB intercistronic spacer reveals a translational motif coincident with the evolution of land plants. J Mol Evol. 2012;75(5–6):184–97.CrossRefPubMedGoogle Scholar
  94. 94.
    Guerriero G, Spadiut O, Kerschbamer C, Giorno F, Baric S, Ezcurra I. Analysis of cellulose synthase genes from domesticated apple identifies collinear genes WDR53 and CesA8A: partial co-expression, bicistronic mRNA, and alternative splicing of CESA8A. J Exp Bot. 2012;63(16):6045–56.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Bahar Halpern K, Veprik A, Rubins N, Naaman O, Walker MD. GPR41 gene expression is mediated by internal ribosome entry site (IRES)-dependent translation of bicistronic mRNA encoding GPR40 and GPR41 proteins. J Biol Chem. 2012;287(24):20154–63.Google Scholar
  96. 96.
    Grabow WW, Jaeger L. RNA self-assembly and RNA nanotechnology. Acc Chem Res. 2014;47:1871–80.CrossRefPubMedGoogle Scholar
  97. 97.
    Gao F, Gulay SP, Kasprzak W, Dinman JD, Shapiro BA, Simon AE. The kissing-loop T-shaped structure translational enhancer of Pea enation mosaic virus can bind simultaneously to ribosomes and a 5′ proximal hairpin. J Virol. 2013;87(22):11987–2002.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Dreher TW. Role of tRNA-like structures in controlling plant virus replication. Virus Res. 2009;139:217–29.CrossRefPubMedGoogle Scholar
  99. 99.
    Lyons AJ, Robertson HD. Detection of tRNA-like structure through RNase P cleavage of viral internal ribosome entry site RNAs near the AUG start triplet. J Biol Chem. 2003;278(29):26844–50.CrossRefPubMedGoogle Scholar
  100. 100.
    Serrano P, Gomez J, Martinez-Salas E. Characterization of a cyanobacterial RNase P ribozyme recognition motif in the IRES of foot-and-mouth disease virus reveals a unique structural element. RNA. 2007;13(6):849–59.CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Piron M, Beguiristain N, Nadal A, Martinez-Salas E, Gomez J. Characterizing the function and structural organization of the 5′ tRNA-like motif within the hepatitis C virus quasispecies. Nucleic Acids Res. 2005;33(5):1487–502.CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Lozano G, Martinez-Salas E. Structural insights into viral IRES-dependent translation mechanisms. Curr Opin Virol. 2015;12:113–20.CrossRefPubMedGoogle Scholar
  103. 103.
    Saghatelian A, Couso JP. Discovery and characterization of smORF-encoded bioactive polypeptides. Nature Chem Biol. 2015;11(12):909–16.CrossRefGoogle Scholar
  104. 104.
    Wellensiek BP, Larsen AC, Stephens B, Kukurba K, Waern K, Briones N, et al. Genome-wide profiling of human cap-independent translation-enhancing elements. Nat Methods. 2013;10(8):747–50.CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Gilbert WV, Zhou K, Butler TK, Doudna JA. Cap-independent translation is required for starvation-induced differentiation in yeast. Science. 2007;317(5842):1224–7.CrossRefPubMedGoogle Scholar
  106. 106.
    Peguero-Sanchez E, Pardo-Lopez L, Merino E. IRES-dependent translated genes in fungi: computational prediction, phylogenetic conservation and functional association. BMC Genom. 2015;16(1):1059.CrossRefGoogle Scholar
  107. 107.
    Lozano G, Fernandez N, Martinez-Salas E. Modeling three-dimensional structural motifs of viral IRES. J Mol Biol. 2016;428(5 Pt A):767–76.Google Scholar
  108. 108.
    Ramos R, Martinez-Salas E. Long-range RNA interactions between structural domains of the aphthovirus internal ribosome entry site (IRES). RNA. 1999;5(10):1374–83.CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Phelan M, Banks RJ, Conn G, Ramesh V. NMR studies of the structure and Mg2+ binding properties of a conserved RNA motif of EMCV picornavirus IRES element. Nucleic Acids Res. 2004;32(16):4715–24.CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Du Z, Ulyanov NB, Yu J, Andino R, James TL. NMR structures of loop B RNAs from the stem-loop IV domain of the enterovirus internal ribosome entry site: a single C to U substitution drastically changes the shape and flexibility of RNA. Biochemistry. 2004;43(19):5757–71.CrossRefPubMedGoogle Scholar
  111. 111.
    Bhattacharyya S, Das S. An apical GAGA loop within 5′ UTR of the Coxsackievirus B3 RNA maintains structural organization of the IRES element required for efficient ribosome entry. RNA Biol. 2006;3(2).Google Scholar
  112. 112.
    Jung S, Schlick T. Candidate RNA structures for domain 3 of the foot-and-mouth-disease virus internal ribosome entry site. Nucleic Acids Res. 2013;41(3):1483–95.CrossRefPubMedGoogle Scholar
  113. 113.
    Fernandez-Miragall O, Ramos R, Ramajo J, Martinez-Salas E. Evidence of reciprocal tertiary interactions between conserved motifs involved in organizing RNA structure essential for internal initiation of translation. RNA. 2006;12(2):223–34.CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Garcia-Martin JA, Dotu I, Clote P. RNAiFold 2.0: a web server and software to design custom and Rfam-based RNA molecules. Nucleic Acids Res. 2015;43(W1):W513–21.CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Dotu I, Lozano G, Clote P, Martinez-Salas E. Using RNA inverse folding to identify IRES-like structural subdomains. RNA Biol. 2013;10(12):1842–52.CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Oldfield CJ, Dunker AK. Intrinsically disordered proteins and intrinsically disordered protein regions. Annu Rev Biochem. 2014;83:553–84.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Rosario Francisco-Velilla
    • 1
  • Gloria Lozano
    • 1
  • Rosa Diaz-Toledano
    • 1
  • Javier Fernandez-Chamorro
    • 1
  • Azman M. Embarek
    • 1
  • Encarnacion Martinez-Salas
    • 1
    Email author
  1. 1.Centro de Biología Molecular Severo OchoaConsejo Superior de Investigaciones Científicas - Universidad Autónoma de MadridMadridSpain

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