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Novel viral translation strategies

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Viral genomes are compact and encode a limited number of proteins. Because they do not encode components of the translational machinery, viruses exhibit an absolute dependence on the host ribosome and factors for viral messenger RNA (mRNA) translation. In order to recruit the host ribosome, viruses have evolved unique strategies to either outcompete cellular transcripts that are efficiently translated by the canonical translation pathway or to reroute translation factors and ribosomes to the viral genome. Furthermore, viruses must evade host antiviral responses and escape immune surveillance. This review focuses on some recent major findings that have revealed unconventional strategies that viruses utilize, which include usurping the host translational machinery, modulating canonical translation initiation factors to specifically enhance or repress overall translation for the purpose of viral production, and increasing viral coding capacity. The discovery of these diverse viral strategies has provided insights into additional translational control mechanisms and into the viral host interactions that ensure viral protein synthesis and replication. WIREs RNA 2014, 5:779–801. doi: 10.1002/wrna.1246 This article is categorized under: Translation > Translation Mechanisms Translation > Translation Regulation
Eukaryotic translation initiation. The 5′ 7‐methyl‐guanosine cap of cellular mRNA is bound by the cap‐binding complex eIF4F, which consists of the cap‐binding protein 4E, the helicase 4A, and the scaffold protein 4G. eIF4G facilitates recruitment of the 43S preinitiation complex (1) and circularization of the mRNA through interaction with poly(A) binding proteins (PABP) bound to the 3′ poly(A) tail. Following 43S recruitment, the complex undergoes ATP‐dependent directional scanning (2) to locate the AUG start codon within a favorable context. (3) Start codon recognition and anticodon:codon pairing results in hydrolysis of the eIF2‐bound GTP in a process mediated by eIF5. Subsequently, eIF5B mediates joining of the 60S ribosomal subunit to form an elongation‐competent 80S ribosome (4). (Reprinted with permission from Ref . Copyright 2004 Nature Publishing Group)
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Increasing coding capacity by programmed ribosomal frameshift elements and IRES‐mediated translational reading frame selection. The translation cycle involves the steps of initiation, characterized by the recruitment and positioning of the ribosome at the translational start site; elongation, where amino acids are sequentially added to the growing polypeptide chain; and termination, where the nascent polypeptide is released from the ribosome. Programmed ribosomal frameshifts (PRFs) act on an elongating ribosome whereas translational reading frame selection mediated by the IGR IRES occurs at the level of initiation. (a) Three types of PRFs, including the −1, +1 and −2 PRFs, have been identified in various viral genomes. In the −1 PRF, the frameshift site is comprised of a heptanucleotide sequence with the consensus X_XXY_YYZ (where X represents any nucleotide, Y represents A or U, Z represents A, C, or U, and the underscores designate the codons in the 0 frame) and a downstream spacer sequence. While the consensus for −1 PRFs is well characterized, the frameshift consensus in +1 PRF is more variable. −1 PRFs require a 3′ stimulatory element and +1 PRFs depend on cis‐elements that facilitate the displacement of the ribosome into an alternate frame. The −2 PRF, recently identified in the arterivirus porcine reproductive and respiratory syndrome virus, produces a transframe fusion (TF). The −2 PRF occurs at a conserved G_GUU_UUU sequence and is stimulated by a conserved downstream CCCANCUCC motif located 11 nucleotides downstream. The mechanism of this mode of frameshift has not been fully elucidated. (b) Israeli acute paralysis virus (IAPV) IGR IRES‐mediated translation in the +1 reading frame occurs via a U:G wobble (highlighted in red) adjacent to the IRES translational start site. The first amino acid decoded in the +1 frame is alanine. Mass spectrometry analysis has identified the presence of ORFx in virally infected honeybees, although its role in virus infection is currently unknown. (Reprinted with permission from Ref . Copyright 2012 Elsevier Inc.)
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Recycling of eIF2 during translation initiation. During translation initiation, the eIF2·Met‐tRNAi·GTP ternary complex is recruited to the 43S preinitiation complex and is involved in start codon recognition (1). Upon cognate codon:anticodon pairing, eIF5 mediates hydrolysis of eIF2‐bound GTP to GDP (2), which must be recycled by the guanine nucleotide exchange factor eIF2B for subsequent rounds of initiation (3). The α‐subunit of eIF2 is susceptible to phosphorylation by various eIF2α kinases (PERK, HRI, PKR, and GCN2) in response to specific environmental triggers. The phosphorylated form of eIF2α acts as a competitive inhibitor of eIF2B (4), thus preventing recycling of the GDP‐bound eIF2 to the GTP‐bound form and decreasing the availability of the ternary complex pool for translation initiation. Interestingly, some viruses including hepatitis C virus (HCV) and alphaviruses utilize alternate initiation factors such as eIF2A and eIF2D to deliver the initiator tRNA (5). This allows viral translation to proceed when the canonical translation initiation pathway through the eIF2·Met‐tRNAi·GTP ternary complex is compromised.
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Specialized ribosomes in viral translation. (a) (Top left) The positions of ribosomal proteins S5 (in cyan) and S25 (in magenta) are shown on the 40S subunit, as viewed from the intersubunit space. Various landmarks of the 40S subunit are indicated (bk = beak, pt = platform, b = body, rf = right foot, lf = left foot). RPS5 and S25 interact with the cricket paralysis virus and hepatitis C virus IRESs. (Top right) The structure as observed after a 90° clockwise rotation. (Bottom) The location of ribosomal protein L40 (in green) within the 80S ribosome is shown. In all structures, the rRNA is shown in gray, 40S ribosomal proteins in yellow, 60S ribosomal proteins in blue, and other ribosomal proteins involved in viral translation mechanisms, as summarized in (b), are shown in purple. Structures are produced using PDB accession numbers: 3U5B, 3U5C, 3U5D, and 3U5D. (Reprinted with permission from Ref . Copyright 2011 American Association for the Advancement of Science) (b) Ribosomal components and/or their modifications that interact with the viral genome or that are shown to be required for viral translation based on structural and biochemical studies.
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Hepatitis C virus (HCV) IRES. (a) Genome organization of the hepatitis C virus. The 5′‐untranslated region of the HCV genome contains an internal ribosome entry site (boxed in purple) that mediates ribosome recruitment using only eIF3 and the eIF2·Met‐tRNAi·GTP ternary complex. The IRES consists of domains II–IV, where the apical region of domain III interacts with eIF3 (shaded in orange), and regions within domains II, III, and IV establish contacts with the ribosome (shaded in gray). The IRES translational start site is highlighted in red. Within the 5′ and 3′ untranslated regions (UTRs) of the viral genome, three miR‐122 binding sites have been identified by base complementarity (sequences highlighted in red). The stop codon of the coding region is highlighted in blue. The structures of the HCV 5′ and 3′ UTRs are Reprinted with permission from Ref . Copyright 2005 American Association for the Advancement of Science. (b) Cryo‐EM structure of the vacant 40S ribosomal subunit from rabbit reticulocytes and 40S‐HCV complex at 20Å. The HCV IRES binds to the solvent accessible side of the ribosome and induces conformational changes in the 40S subunit, similar to those induced by IGR IRES‐40S binding (indicated by asterisks). (Reprinted with permission from Ref . Copyright 2001 American Association for the Advancement of Science). (c) Cryo‐EM structure of the 40S‐eIF3 (11.6 Å) and 40S‐CSFV ΔII IRES‐eIF3 (9.5 Å) complexes containing eIF3 and 40S from rabbit reticulocytes. In the 40S‐eIF3 complex (right), eIF3 (shown in red) interacts directly with the 40S subunit (in yellow). In contrast, eIF3 binds to the IRES (in blue) via the apical loop of domain III in the IRES‐containing complex (left), suggesting that the IRES displaces eIF3 to gain access to the ribosome. (Reprinted with permission from Ref . Copyright 2013 Nature Publishing Group)
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Dicistrovirus intergenic region internal ribosome entry site (IGR IRES). (a) Genome organization of members of the Dicistroviridae family. Dicistroviruses have a single‐stranded, positive‐sense RNA genome that contains the genome‐linked protein (Vpg) and poly(A) tail at the 5′‐ and 3′‐ends, respectively. The genome contains two non‐overlapping open reading frames. The upstream cistron (encoding viral nonstructural proteins) is regulated by the 5′ IRES, while the downstream cistron (encoding viral structural proteins) is expressed under the regulation of the IGR IRES (boxed). The IGR IRES can directly recruit ribosomes in the absence of canonical translation initiation factors. (b) Sequence and secondary structure of the CrPV IGR IRES. The IGR IRES adopts a triple‐pseudoknotted structure (PKI/II/III) with two independently folded domains: the ribosome binding domain (boxed in blue) and tRNA‐mimicry domain. Within the ribosome binding domain, stem‐loop (SL) V interacts with ribosomal protein (RP) S5 whereas SL IV interacts with RPS25 (shaded in gray). The conserved L1.1 bulge is thought to interact with the L1 stalk of the 60S subunit to direct 80S formation. Notable structural elements are boxed in the corresponding colors as those used in crystal structure in (c). The tRNA‐mimicry domain structurally mimics an authentic codon:anticodon interaction and establishes the translational reading frame by occupying the ribosomal P site. IRES‐mediated translation initiates from the A site and at a non‐AUG codon to direct synthesis of the viral structural proteins. The IRES codon:anticodon‐like interaction is boxed in green. Specific nucleotides within this region are depicted in the corresponding colors as the structure shown in (d). (Reprinted with permission from Ref . Copyright 2010 Cold Spring Harbor Laboratory Press) (c) Crystal structure of the ribosome binding domain from the Plautia stali intestinal virus. The ribosome binding domain forms a solvent‐inaccessible core that mediates contacts with the 40S ribosomal subunit. (Reprinted with permission from Ref . Copyright 2006 American Association for the Advancement of Science) (d) Comparison of the CrPV PKI codon:anticodon‐like interaction and an authentic P‐site mRNA:tRNA interaction. Analogous bases in both structures are highlighted in the same color. (Reprinted with permission from Ref . Copyright 2008 Nature Publishing Group) (e) Cryo‐EM reconstructions of the vacant human 40S ribosomal subunit (left) and the CrPV IGR IRES‐bound 40S complex (right) at 25.3 Å and 20.3 Å, respectively. The IGR IRES binds to the intersubunit space and induces conformational changes in the 40S subunit (indicated by asterisk). (Reprinted with permission from Ref . Copyright 2004 Cell Press)
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