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Regulation of gene expression for translation initiation factor eIF-2 alpha: importance of the 3' untranslated region.

ABSTRACT: Gene expression of the alpha-subunit of eukaryotic initiation factor-2 (eIF-2 alpha), involves transcriptional and post-transcriptional mechanisms. eIF-2 alpha is a single-copy gene expressing two mRNAs, 1.6 and 4.2 kb in size. Cloning and sequencing of the cDNA for the 4.2 kb mRNA revealed that it is the result of alternative polyadenylation site selection. Four polyadenylation sites were identified within the 3' untranslated region (UTR) of eIF-2 alpha, only two of which are normally utilized in human and mouse tissues. A functional role for the extended 3' UTR was assessed by comparing the translatability and stability of the 1.6 and 4.2 kb mRNAs. Both the 1.6 and 4.2 kb transcripts could be translated in vitro and were identified in vivo as being distributed on large polyribosomes. This indicates that both mRNAs are efficiently translated. Stability studies showed that in activated T-cells the 4.2 kb mRNA was more stable than the 1.6 kb mRNA. Polyadenylation site selection and mRNA stability differ for the two mRNAs of eIF-2 alpha. These activities might be modulated by sequence elements contained within the untranslated regions of the eIF-2 alpha gene.

SUBMITTER: Miyamoto S

PROVIDER: S-EPMC1217276 | biostudies-other | 1996 May

REPOSITORIES: biostudies-other

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Project description:The 5' untranslated region (UTR) of hepatitis C virus (HCV), which is composed of four domains (I, II, III, and IV) and a pseudoknot, is essential for translation and viral replication. Equine nonprimate hepacivirus (EHcV) harbors a 5' UTR consisting of a large 5'-terminal domain (I); three additional domains (I', II, and III), which are homologous to domains I, II, and III, respectively, of HCV; and a pseudoknot, in the order listed. In this study, we investigated the roles of the EHcV 5' UTR in translation and viral replication. The internal ribosome entry site (IRES) activity of the EHcV 5' UTR was lower than that of the HCV 5' UTR in several cell lines due to structural differences in domain III. Domains I and III of EHcV were functional in the HCV 5' UTR in terms of IRES activity and the replication of the subgenomic replicon (SGR), although domain II was not exchangeable between EHcV and HCV for SGR replication. Furthermore, the region spanning domains I and I' of EHcV (the 5'-proximal EHcV-specific region) improved RNA stability and provided the HCV SGR with microRNA 122 (miR-122)-independent replication capability, while EHcV domain I alone improved SGR replication and RNA stability irrespective of miR-122. These data suggest that the region spanning EHcV domains I and I' improves RNA stability and viral replication regardless of miR-122 expression. The 5'-proximal EHcV-specific region may represent an inherent mechanism to facilitate viral replication in nonhepatic tissues.IMPORTANCE EHcV is the closest viral homolog to HCV among other hepaciviruses. HCV exhibits a narrow host range and liver-specific tropism, while epidemiological reports suggest that EHcV infects the liver and respiratory organs in horses, donkeys, and dogs. However, the mechanism explaining the differences in host or organ tropism between HCV and EHcV is unknown. In this study, our data suggest that the 5' untranslated region (UTR) of EHcV is composed of an internal ribosome entry site (IRES) element that is functionally exchangeable with HCV IRES elements. Furthermore, the 5'-proximal EHcV-specific region enhances viral replication and RNA stability in a miR-122-independent manner. Our data suggest that the region upstream of domain II in the EHcV 5' UTR contributes to the differences in tissue tropism observed between these hepaciviruses.

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Regulation of gene expression for translation initiation factor eIF-2 alpha: importance of the 3' untranslated region.

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