Abstract
Sindbis virus (SINV) contains an RNA genome of positive polarity with two open reading frames (ORFs). The first ORF is translated from the genomic RNA (gRNA), rendering the viral non-structural proteins, whereas the second ORF is translated from a subgenomic mRNA (sgRNA), which directs the synthesis of viral structural proteins. SINV infection strongly inhibits host cell translation through a variety of different mechanisms, including the phosphorylation of the eukaryotic initiation factor eIF2α and the redistribution of cellular proteins from the nucleus to the cytoplasm. A number of motifs have been identified in SINV sgRNA, including a hairpin downstream of the AUG initiation codon, which is involved in the translatability of the viral sgRNA when eIF2 is inactivated. Moreover, a 3′-UTR motif containing three stem-loop structures is involved in the enhancement of translation in insect cells, but not in mammalian cells. Accordingly, SINV sgRNA has evolved several structures to efficiently compete for the cellular translational machinery. Mechanistically, sgRNA translation involves scanning of the 5′-UTR following a non-canonical mode and without the requirement for several initiation factors. Indeed, sgRNA-directed polypeptide synthesis occurs even after eIF4G cleavage or inactivation of eIF4A by selective inhibitors. Remarkably, eIF2α phosphorylation does not hamper sgRNA translation during the late phase of SINV infection. SINV sgRNA thus constitutes a unique model of a capped viral mRNA that is efficiently translated in the absence of several canonical initiation factors. The present review will mainly focus in the non-canonical mechanism of translation of SINV sgRNA.
Highlights
Sindbis virus (SINV) belongs to the alphavirus genus in the Togaviridae family and contains a positive-strand RNA genome [1]
Distinct mechanisms have been suggested to account for the abrogation of cellular protein synthesis by alphaviruses: (1) The phosphorylation of the α-subunit of eIF2; (2) Competition of viral mRNAs for the host translational machinery; and (3) Modifications of the cytoplasmic ionic environment. eIF2 plays a central role in mRNA translation and binds Met-tRNAi Met and GTP to form a ternary complex that interacts with the AUG initiation codon and delivers the initiator Met-tRNAi Met to the P site of the 40S ribosomal subunit
A number of new translation not affect protein synthesis directed by subgenomic mRNA (sgRNA), reinforcing the concept that the eIF4F complex is not inhibitors have been discovered through high-throughput screening methods [146]
Summary
Sindbis virus (SINV) belongs to the alphavirus genus in the Togaviridae family and contains a positive-strand RNA genome [1]. The alphavirus genus comprises ~30 virus species that are transmitted by arthropods, typically mosquitoes, to a range of vertebrate hosts [2]. SINV and SFV have been widely used in the laboratory as model systems to study protein synthesis, transcription and replication at the molecular level, and to understand viral pathogenesis and the interaction of these viruses with their hosts. In this regard, fundamental aspects of translation regulation in virus-infected cells have been uncovered using SINV and SFV. We will summarize what is known about the mechanisms of translation of SINV mRNAs, with a focus on the initiation events of non-canonical translation of subgenomic mRNA (sgRNA)
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