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Viral internal ribosomal entry sites: four classes for one goal

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To ensure efficient propagation, viruses need to rapidly produce viral proteins after cell entrance. Since viral genomes do not encode any components of the protein biosynthesis machinery, viral proteins must be produced by the host cell. To hi‐jack the host cellular translation, viruses use a great variety of distinct strategies. Many single‐stranded positive‐sensed RNA viruses contain so‐called internal ribosome entry sites (IRESs). IRESs are structural RNA motifs that have evolved to specific folds that recruit the host ribosomes on the viral coding sequences in order to synthesize viral proteins. In host canonical translation, recruitment of the translation machinery components is essentially guided by the 5′ cap (m7G) of mRNA. In contrast, IRESs are able to promote efficient ribosome assembly internally and in cap‐independent manner. IRESs have been categorized into four classes, based on their length, nucleotide sequence, secondary and tertiary structures, as well as their mode of action. Classes I and II require the assistance of cellular auxiliary factors, the eukaryotic intiation factors (eIF), for efficient ribosome assembly. Class III IRESs require only a subset of eIFs whereas Class IV, which are the more compact, can promote translation without any eIFs. Extensive functional and structural investigations of IRESs over the past decades have allowed a better understanding of their mode of action for viral translation. Because viral translation has a pivotal role in the infectious program, IRESs are therefore attractive targets for therapeutic purposes. WIREs RNA 2018, 9:e1458. doi: 10.1002/wrna.1458 This article is categorized under: Translation > Ribosome Structure/Function Translation > Translation Mechanisms RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes
Hepatitis C virus (HCV), a class III internal ribosome entry site (IRES). (a) Secondary structure of the IRES from Hepatitis C Virus. AUG start codon is shown in yellow. 3D structures of the IRES domains and subdomains are shown. They have been obtained either by NMR (N) or crystallography (X). For X‐ray structures, the resolution is indicated. (b) 3D models of the complete HCV IRES based on the structures of isolated domains, domains II, and III and highly flexible.
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Foot and Mouth Disease virus (FMDV), a class II internal ribosome entry site (IRES).

Secondary structure of the 5′UTR of FMDV genomic RNA. Nucleotides that are critical for IRES activity or for specific trans‐acting factor recruitments are shown in orange. Domain IV specifically recruits eIF4G (dark green) and domain V interacts with eIF4B, PTB, and other RNA‐binding proteins (shown in blue). AUG start codons are shown in yellow. No structural data have been obtained on this IRES.

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Encephalomyocarditis virus (EMCV), a class II internal ribosome entry site (IRES).

Secondary structure of the 5′UTR of Encephalomyocarditis viral genomic RNA. Nucleotides that are critical for IRES activity or for specific trans‐acting factor recruitments are shown in orange. The minimal IRES domain is shown in a dashed square. Domain IV specifically recruits eIF4G (dark green) and domain V interacts with eIF4B, PTB, and other RNA‐binding proteins (shown in blue). AUG start codons are shown in yellow. Structural data obtained on the domain IV alone by NMR (N) or on the complex IV with the HEAT‐1 domain of eIF4G (by SAXS) are shown on the right. (Reprinted with permission from Ref . © 2016 Nature America Inc.).

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Poliovirus (PV), a class I internal ribosome entry site (IRES). Secondary structure of the 5′UTR from PV genomic RNA. The 5′ cloverleaf structure (CL) is involved in viral replication (light green). Nucleotides that are critical for IRES activity or that are required for specific trans‐acting factor recruitments are shown in orange. The minimal IRES domain is shown in a dashed square. The domain V that interacts specifically with eIF4G is shown in dark green. AUG start codons are shown in yellow. Structural data obtained by NMR (N) with RNA subdomains are shown with the same color code.
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Virus classification. Orders and virus families that contain internal ribosome entry site (IRES) elements are highlighted in green. Examples of species that contain the better described IRES elements are shown on the right. Data extracted from ICTV, Virus Taxonomy 2016 Release (EC48, Budapest Hungary, August 2016; Email ratification 2017 (MSL #31))****.
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Canonical cap‐dependent translation initiation. Eukaryotic translation initiation is a sophisticated multistep process that requires numerous trans‐acting factors (eIFs, eIF1, eIF1a, eIF2, eIF2B, eIF3, eIF4A, eIF4B, eIF4E, eIF4G, eIF5, and eIF5B) that assist the ribosome in order to localize the AUG start codon. Interaction between 4G and PABP allows 5′→3′ circularization of capped‐polyadenylated mRNA. The whole process requires ATP for 5′→3′ scanning and GTP for AUG recognition.
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Structures of Hepatitis C Virus (HCV) internal ribosome entry site (IRES) with the ribosome.

(a) Cryo‐EM structures of ribosomal complexes with CrPV IGR IRES. (b) Movement of L1‐stalk in the complexes with IGR. (c) Translocation of PKI from the A to the P site of the ribosome induced by eEF2. (d) PKI mimics the codon–anticodon duplex in the P site of the ribosome. (e) Specific contacts between PKI and eEF2.

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Cricket Paralysis Virus (CrPV), a class IV internal ribosome entry site (IRES).

(a) Secondary structure of the IRES from Cricket Paralysis Virus. The first codon is shown in yellow. 3D Structures of the IRES domains and subdomains are shown. They have been obtained by crystallography (X), the resolution is indicated. The IRES contains three pseudoknots that are shown in orange. Two types of domain 3 are represented, type I from CrPV and type II from TSV. (b) Specific contacts between the CrPV IRES and the small ribosomal subunit 40S and the large ribosomal subunit 60S. The ribosomal proteins and rRNA domains are shown in orange.

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Structures of Hepatitis C Virus (HCV) internal ribosome entry site (IRES) with the ribosome.

(a) Cryo‐EM structures of ribosomal complexes with HCV IRES. Specific contacts between the IRES and the 40S ribosomal subunit are shown on the right. (b) Closer view of specific interactions between eS27 and domains IIIa and IIIc, ES7 and domain IIIe, domain IIb, and uS7/uS11. (c) Movement of domain II in the E site of the ribosome allows accurate positioning of Met‐tRNAMeti in the P site of the ribosome.

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Hepatitis C Virus (HCV) internal ribosome entry site (IRES) trans‐acting factors.

Nucleotides that are critical for specific trans‐acting factor recruitments are shown in orange. The minimal IRES domain is shown in a dashed square. Domain II, IIId, IIIe, and IIIf specifically recruits small ribosomal subunit 40S (shown in gray) and domain III interacts with eIF3 (shown in purple). Specific contacts with the ribosomal proteins and rRNA are indicated. The ribosomal AUG start codon is shown in yellow.

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