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Alteraciones de la Expresión Génica Inducidas por Proteasas Virales

AutorCastelló, Alfredo
DirectorCarrasco, Luis
Fecha de publicación2008
EditorUniversidad Autónoma de Madrid
ResumenViruses rely on the cellular machinery to synthesize their proteins, since this complex process requires numerous components that cannot all be encoded by viral genomes. Thus, viral mRNAs have to compete with host mRNAs for ribosomes and other components of the translation machinery. To achieve this goal, viruses have developed sophisticated mechanisms to maximize the translation of their own mRNAs by inhibiting host cell protein synthesis. Since the initiation of translation is a major step in the regulation of gene expression in eukaryotic cells, viruses usually target this step to block cellular mRNAs translation, thereby ensuring the synthesis of viral proteins. A number of viral proteases is involved in the proteolysis of translation initiation factors, such as eIF4G and PABP. Under these conditions the association of host mRNAs to ribosomes is severely impaired, whereas some viral mRNAs can interact efficiently with the translational machinery. eIF4GI cleavage by poliovirus 2Apro does not inhibit endogenous cellular translation. However, when eIF4GII is also cleaved by this protease, host protein synthesis is inhibited deeply. In fact, eIF4GII could support initiation of translation since the proteolysis of this factor in BHK cells correlates with the inhibition of the cellular mRNA translation. Nevertheless, translation of a de novo synthesized luciferase mRNA is blocked in concomitance with eIF4GI cleavage. Thus, eIF4GI could play a different role in the initiation of translation. On the other hand, PABP is hydrolyzed in HIV-infected cells. The cleavage of this protein is mediated directly by HIV-1 PR. Thus, we observe that 2Apro as well as HIV-1 protease inhibit host protein synthesis using different mechanisms. 2Apro cleaves both eIF4GI and eIF4GII, whereas HIV-1 PR proteolyzes eIF4GI and PABP. Both combinations impair cap- and poly(A)- dependent translation, while under these conditions picornavirus IRES-driven translation is enhanced or is not affected. Poliovirus 2Apro and HIV-1 PR does not inhibit sindbis virus subgenomic mRNA translation, despite the fact that eIF4GI, eIF4GII and PABP are cleaved in infected cells. The Leader sequence from the subgenomic SV mRNA is necessary for this translational behaviour. Finally, poliovirus 2Apro impairs mRNA export from the nucleus to the cytoplasm. Notably, eIF4GI C-terminal product is accumulated in the nucleus. eIF4GI does not participate in mRNA export since depletion of this factor with siRNAs does not affect the distribution of mRNAs in the cell. Poliovirus 2Apro also disables pre-mRNA splicing. In particular, the stage affected by the viral activity during the splicing is the liberation of 3´ extreme of the intron. These findings could help to understand the mechanism by which poliovirus alters gene expression in infected cells.
DescripciónTesis doctoral inédita. Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular
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