Animal virus schemes for translation dominance - PubMed (original) (raw)

Review

Animal virus schemes for translation dominance

Lucas C Reineke et al. Curr Opin Virol. 2011 Nov.

Abstract

Viruses have adapted a broad range of unique mechanisms to modulate the cellular translational machinery to ensure viral translation at the expense of cellular protein synthesis. Many of these promote virus-specific translation by use of molecular tags on viral mRNA such as internal ribosome entry sites (IRES) and genome-linked viral proteins (VPg) that bind translation machinery components in unusual ways and promote RNA circularization. This review describes recent advances in understanding some of the mechanisms in which animal virus mRNAs gain an advantage over cellular transcripts, including new structural and biochemical insights into IRES function and novel proteins that function as alternate met-tRNA(i)(met) carriers in translation initiation. Comparisons between animal and plant virus mechanisms that promote translation of viral mRNAs are discussed.

Keywords: IRES; animal virus; eIF2-independent; internal ribosome entry; translation initiation.

PubMed Disclaimer

Figures

Figure 1

Schematic depiction of translation initiation and the eIF2 nucleotide exchange cycle. Eukaryotic initiation factor 4F, which consists of the cap binding protein (eIF4E), a scaffolding protein (eIF4G) and an RNA helicase (eIF4A), recognizes the m7G cap structure. The mRNA can circularize in accordance with the closed-loop model via interaction between PABP at the 3′ terminus and eIF4G complexed with the 5′ cap. Next, the 43S preinitiation complex, composed of the 40S small ribosomal subunit and initiation factors eIF1, eIF1A, heterotrimeric eIF2(α,β,γ), eIF5 and multisubunit eIF3, can bind the mRNA via interaction between eIF3 and eIF4G to form the 48S complex. eIF2 delivers the initiator methionyl tRNA as a ternary complex, comprised of eIF2·GTP·met-tRNAimet. The 40S ribosomal subunit then scans to locate the AUG codon where the 60S joins, some factors are ejected including eIF2, and the 80S ribosome enters the elongation phase of protein synthesis (reviewed in [109]). eIF2 activity relies on GTP hydrolysis and the guanine nucleotide exchange factor eIF2B must recycle GTP·eIF2 before it can be used in subsequent rounds of translation initiation (depicted by the eIF2:GTP exchange cycle). Several kinases have been identified that act on eIF2 to inhibit met-tRNAimet delivery by phosphorylating eIF2α, which include: PKR, a double-stranded RNA-dependent protein kinase typically activated during infection by RNA viruses in animals, PERK, which is activated in response to ER stress, HRI, a heme-sensing molecule, and GCN2, which senses nutrient availability.

Figure 2

Initiation on virus internal ribosome entry sites (IRES). Virus IRESs use various non-canonical interactions with initiation factors and/or the 40S ribosome subunit. eIF4E is not involved in the binding of viral IRESs shown. Type 1 and 2 IRESs bind the central heat domain of eIF4GI in an analogous position and orientation on stem loop structures adjacent to conserved oligopyrimidine-spacer-AUG motifs (Yn-Xm-AUG) at the 3′ border of the IRES elements. The AUG codon basepairs with the initiator tRNA delivered by eIF2. eIF4GI binding is stimulated by eIF4A and modulated by PTB, which binds the same stem-loop structure as eIF4GI in Type 1 IRESs and binds a more diffuse footprint of RNA domains in Type 2 IRESs [31••, 33]. PV Type 1 IRES requires SRp20 for PCBP2 ITAF function and may play a role in bridging the IRES to the 43S complex [26]. Type 3 IRESs and the unclassified HIV2 IRES utilize interactions between eIF3 and 40S. The HCV pseudoknot (shaded in grey) positions the initiation codon (green box) in the mRNA binding cleft of the 40S subunit [36] and the apical stem loops of domain III interact directly with eIF3 [110, 111, 112]. HIV2 IRES contains 4 domains conserved among primate lentiviruses (shaded, P3, P4, P2–P5). HIV2 IRES can bind 48S preinitiation complexes at three AUGs (green boxes) [16]; however, eIF1 is not found in these complexes [37].

Figure 3

eIF5B and other eIF2-independent mechanisms for translation initiation. (A) The crystal structure of archaeal IF2/eIF5B is organized into 4 highly conserved domains (labeled 1-IV). (B) Mammalian eIF5B contains the C-terminal half that is homologous to archaeal IF2 and a N-terminal regulatory domain whose structure is unknown that is removed by PV 3Cpro cleavage. (C) Infection and stress activate eIF2α kinases that reduce concentrations of eIF2·GTP·met-tRNAimet ternary complex, inhibiting translation from viral IRES elements. PV and HCV may overcome this restriction by recruiting alternate proteins to help deliver met-tRNAimet in GTP-dependent or GTP-independent mechanisms.

References

1. Lopez-Lastra M., Ramdohr P., Letelier A., Vallejos M., Vera-Otarola J., Valiente-Echeverria F. Translation initiation of viral mRNAs. Rev Med Virol. 2010;20:177–195. - PMC - PubMed
2. An excellent review of viral mechanisms of translational control.
1. Gallie D.R. A tale of two termini: a functional interaction between the termini of an mRNA is a prerequisite for efficient translation initiation. Gene. 1998;216:1–11. - PubMed
1. Mazumder B., Seshadri V., Fox P.L. Translational control by the 3′-UTR: the ends specify the means. Trends Biochem Sci. 2003;28:91–98. - PubMed
1. Amrani N., Ghosh S., Mangus D.A., Jacobson A. Translation factors promote the formation of two states of the closed-loop mRNP. Nature. 2008;453:1276–1280. - PMC - PubMed
1. Bonderoff J.M., Lloyd R.E. Time-dependent increase in ribosome processivity. Nucleic Acids Res. 2010;38:7054–7067. - PMC - PubMed

Animal virus schemes for translation dominance - PubMed (original) (raw)