The Regulation of Translation in Alphavirus-Infected Cells

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.

Silvestrol Inhibits Chikungunya Virus Replication

“…The shut-off of host protein synthesis by the virus prevents the production of antiviral proteins, such as interferons. Translation of cellular and gmRNA is downregulated during late phases of infection, when sgmRNA synthesizes structural proteins very efficiently [ 34 ]. Translation of mRNAs also requires the initiation factor eIF2α.…”

A Retrospective on eIF2A—and Not the Alpha Subunit of eIF2

“…In 2006, Iván Ventoso, Luis Carrasco and their co-authors suggested that eIF2A might be involved in the initiation of translation of subgenomic (26S) Sindbis virus (SV) mRNA [84]. SV infection induces PKR activation, which results in a strong phosphorylation (95%) of eIF2α leading to its inactivation [86]. To test the involvement of eIF2A in translation of SV 26S mRNA, the authors silenced the expression of eIF2A by means of siRNA interference and found that abrogation of eIF2A expression led to a reduction in the synthesis of SV structural proteins in PKR +/+ cells (that allowed for eIF2α phosphorylation upon viral infection), but not in PKR 0/0 cells [84].…”

Unconventional RNA‐binding proteins step into the virus–host battlefront

“…A stem-loop structure present at the 5 0 end of this mRNA is required for efficient translation (McInerney, Kedersha, Kaufman, Anderson, & Liljestrom, 2005;Ventoso et al, 2006). Thus, novel cap-binding proteins such as EIF3D may replace the EIF4F complex and promote viral translation after activation by the hairpin structure (Carrasco et al, 2018).…”