title: The 5' untranslated region of the human T-cell lymphotropic virus type 1 mRNA enables cap-independent translation initiation.
abstract: The human T-cell leukemia virus type 1 (HTLV-1) is a complex human retrovirus that causes adult T cell leukemia and of HTLV-associated myelopathy/tropical spastic paraparesis. The mRNA of some complex retroviruses, including the human and simian immunodeficiency viruses (HIV and SIV), can initiate translation using a canonical cap-dependent mechanism or through an internal ribosome entry site (IRES). In this study, we present strong evidence showing that like HIV-1 and SIV, the 5'-untranslated region (5'UTR) of the HTLV-1 full-length mRNA harbors an IRES. Cap-independent translational activity was evaluated and demonstrated using dual luciferase bicistronic mRNAs in rabbit reticulocyte lysate, in mammalian cell culture, and in Xenopus laevis oocytes. Characterization of the HTLV-1 IRES shows that its activity is dependent on the ribosomal protein S25 (RPS25) and that its function is highly sensitive to the drug edeine. Together, these findings suggest that the 5'UTR of the HTLV-1 full-length mRNA enables internal recruitment of the eukaryotic translation initiation complex. However, the recognition of the initiation codon requires ribosome scanning. These results suggest that, after internal recruitment by the HTLV-1 IRES, a scanning step takes place for the 40S ribosomal subunit to be positioned at the translation initiation codon.
  
  
  OBJECTIVE
  The mechanism by which retroviral mRNAs recruit the 40S ribosomal subunit internally is not understood. This study provides new insights into the mechanism of translation initiation used by the human T-cell lymphotropic virus type 1 (HTLV-1). The results show that the HTLV-1 mRNA can initiate translation via a noncanonical mechanism mediated by an internal ribosome entry site (IRES). This study also provides evidence showing the involvement of cellular proteins in HTLV-1 IRES-mediated translation initiation. Together, the data presented in this report significantly contribute to the understanding of HTLV-1 gene expression.
authors.affiliation: Laboratorio de Virología Molecular, Instituto Milenio de Inmunología e Inmunoterapia, Centro de Investigaciones Médicas, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Olivares
authors.forename: Dori M
authors.initials: DM
authors.lastname: Landry
authors.forename: C Joaquín
authors.initials: CJ
authors.lastname: Cáceres
authors.forename: Karla
authors.initials: K
authors.lastname: Pino
authors.forename: Federico
authors.initials: F
authors.lastname: Rossi
authors.forename: Camilo
authors.initials: C
authors.lastname: Navarrete
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Huidobro-Toro
authors.forename: Sunnie R
authors.initials: SR
authors.lastname: Thompson
authors.forename: Marcelo
authors.initials: M
authors.lastname: López-Lastra
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D017931:DNA Primers / Q000235:genetics; D004486:Edeine; D006367:HeLa Cells; D015368:Human T-lymphotropic virus 1 / Q000235:genetics*; D006801:Humans; D008156:Luciferases; D009865:Oocytes / Q000378:metabolism; D010442:Peptide Chain Initiation, Translational / Q000235:genetics / Q000502:physiology*; D010957:Plasmids / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism*; D011817:Rabbits; D014982:Xenopus laevis
chemical_list: D020121:5' Untranslated Regions; D017931:DNA Primers; D012333:RNA, Messenger; D004486:Edeine; D008156:Luciferases