Factores de iniciación implicados en la traducción de mRNAS virales. Importancia de los motivos estructurales en el RNA
Autor (es)
González Almela, Esther MaríaEntidad
UAM. Departamento de Biología Molecular; Centro de Biología Molecular Severo Ochoa (CBM)Fecha de edición
2019-09-03Financiado por
El trabajo presentado ha sido financiado por los proyectos SAF2015-66170-R y BFU2012-31861 otorgados por la Dirección General de Investigación Científica y Técnica, Ministerio de Economía y Competitividad.Materias
Traducción genética - Tesis doctorales; Genética vírica - Tesis doctorales; Biología y Biomedicina / BiologíaNota
Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de BIología Molecular. Fecha de lectura: 03-09-2019Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Resumen
Alphaviruses are positive polarity single-stranded RNA viruses responsible for
several human and other animal diseases, causing usually arthrosis or encephalitis that
continue to be a worldwide health threat. They are usually transmitted by blood-sucking
arthropods to vertebrate hosts. Sindbis virus (SINV) is a well-characterized member of
this group and is usually employed as a model system in molecular virology. SINV RNA
genome contains two open reading frames (ORFs) that correspond to the translation of
the genomic RNA (gRNA) and subgenomic RNA (sgRNA), translated at early or late times
post-infection, respectively. SINV infection profoundly blocks cellular protein synthesis
while sgRNA translation occurs, which follows a non-canonical mechanism, independent
of several eukaryotic initiation factors (eIFs), which involves the scanning of 5’-UTR.
In this work, we have studied the requirement of different eIFs for SINV mRNAs
translation. We have examined the role of the RNA helicase eIF4A using the selective
inhibitor pateamine A. Translation of SINV gRNA involves the participation of eIF4A,
while translation of sgRNA is independent of this factor in infected cells but dependent
in transfected cells or in cell-free systems, indicating a dual mechanism of translation.
Moreover, sgRNA translation does not require eIF2, and the identification of substitute
factors has been the object of intensive research in the past few years. eIF2A and eIF2D
were proposed as candidates by several studies. However, we have demonstrated that
eIF2A and eIF2D are not required for the translation of SINV mRNAs, even when eIF2α
is phosphorylated. In addition, eIF2A and eIF2D do not participate in the translation of
SINV sgRNA bearing non-AUG codons. The initiation on non-AUG codons for sgRNA
translation is highly dependent on the integrity of a downstream stable hairpin (DSH)
structure located in the coding region of capsid protein.
Furthermore, in collaboration with Dr. A. Castelló (University of Oxford), we have
demonstrated that the loss of cellular mRNAs and the emergence of viral RNA induced
by SINV infection alters the dynamics and activity of the compendium of RNA-biding
proteins (RBPs) of the host cell. Many of the RBPs whose activity is stimulated by SINV
redistribute to viral replication factories and regulate the capacity of the virus to infect.
Finally, we examined the involvement of several eIFs in hepatitis C virus (HCV)
IRES-driven translation in human cells in a comparative analysis with mRNAs bearing the
encephalomyocarditis virus or the Cricket paralysis virus IRES elements. We concluded
that eIF2, eIF2A, eIF2D, eIF4A and eIF4G are not involved in the initiation of translation
driven by HCV IRES.
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