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Review
. 2013 Jan 1;5(1):a012351.
doi: 10.1101/cshperspect.a012351.

Tinkering with translation: protein synthesis in virus-infected cells

Derek Walsh  1 , Michael B Mathews, Ian Mohr
Affiliations
Review

Tinkering with translation: protein synthesis in virus-infected cells

Derek Walsh et al. Cold Spring Harb Perspect Biol. .

Abstract

Viruses are obligate intracellular parasites, and their replication requires host cell functions. Although the size, composition, complexity, and functions encoded by their genomes are remarkably diverse, all viruses rely absolutely on the protein synthesis machinery of their host cells. Lacking their own translational apparatus, they must recruit cellular ribosomes in order to translate viral mRNAs and produce the protein products required for their replication. In addition, there are other constraints on viral protein production. Crucially, host innate defenses and stress responses capable of inactivating the translation machinery must be effectively neutralized. Furthermore, the limited coding capacity of the viral genome needs to be used optimally. These demands have resulted in complex interactions between virus and host that exploit ostensibly virus-specific mechanisms and, at the same time, illuminate the functioning of the cellular protein synthesis apparatus.

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Figures

Figure 1.
Figure 1.
Recruitment of 40S ribosome subunits to viral mRNAs: structural features and initiation factor targets. RNA structural elements involved in recruiting cellular 40S ribosome subunits to the 5′ end of viral mRNAs are shown on the left, with their corresponding name immediately to the right. The primary eukaryotic translation initiation factor (eIF) targets involved in recognizing each structural element and recruiting additional factors or mediating 40S subunit binding are indicated, with representative viruses that use them. (?) indicates that the precise factor targeted by hantavirus N protein remains unknown. Abbreviations: MNeSV, Maize necrotic streak virus; BYDV, Barley yellow dwarf virus; PEMV, Pea enation mosaic virus.
Figure 2.
Figure 2.
Control of translation by virus-encoded functions that regulate assembly of eIF4F. (A) eIF4E (4E) is able to interact with eIF4G and assemble the multi-subunit eIF4F complex (4E, 4A, 4G) on the m7GTP-capped (orange ball) mRNA 5′ end. eIF4F assembly typically results in eIF4E phosphorylation by the eIF4G-associated kinase Mnk and recruits eIF3 bound to the 40S ribosome subunit together with associated factors in the 43S complex. PABP is depicted bound to the 3′-poly(A) tail and associates with eIF4G to stimulate translation. Virus-encoded factors that activate (green, on the left) and repress (red, to the right) cellular functions are shown. (B) Cell signaling pathways that control the activity of the translational repressor 4E-BP1 and regulate eIF4F assembly allow for rapid changes in gene expression programs in response to a variety of physiological cues, including viral infection. In response to growth factor–stimulated receptor tyrosine kinases (RTK), PI-3-kinase (PI3K) and mTORC2 activate Akt by phosphorylation on T308 and S473, which, in turn, represses the tuberous sclerosis complex (TSC) by phosphorylating the TSC2 subunit. TSC is a GTPase-activating protein (GAP) that limits the activity of Rheb by promoting Rheb·GDP accumulation, which represses mTORC1. Whereas AMPK and hypoxia stimulate TSC GAP activity to inhibit mTORC1, Receptor Tyrosine Kinase (RTK)–mediated Akt activation inhibits TSC, resulting in mTORC1 activation. Inhibiting TSC allows rheb·GTP accumulation and mTORC1 activation, and results in p70S6K and 4E-BP1 phosphorylation. By stimulating ribosomal protein S6 phosphorylation (rpS6), p70 S6K activation by mTORC1 stimulates the eIF4A-accessory factor eIF4B and inhibits eukaryotic elongation factor 2 (eEF2) kinase, stimulating elongation. Normally, p70 S6K activation represses PI3-kinase (PI3K) to feedback and limit mTORC1 activation. 4E-BP1 hyperphosphorylation (depicted as circled P) relieves translational repression and releases eIF4E.
Figure 2.
Figure 2.
Control of translation by virus-encoded functions that regulate assembly of eIF4F. (A) eIF4E (4E) is able to interact with eIF4G and assemble the multi-subunit eIF4F complex (4E, 4A, 4G) on the m7GTP-capped (orange ball) mRNA 5′ end. eIF4F assembly typically results in eIF4E phosphorylation by the eIF4G-associated kinase Mnk and recruits eIF3 bound to the 40S ribosome subunit together with associated factors in the 43S complex. PABP is depicted bound to the 3′-poly(A) tail and associates with eIF4G to stimulate translation. Virus-encoded factors that activate (green, on the left) and repress (red, to the right) cellular functions are shown. (B) Cell signaling pathways that control the activity of the translational repressor 4E-BP1 and regulate eIF4F assembly allow for rapid changes in gene expression programs in response to a variety of physiological cues, including viral infection. In response to growth factor–stimulated receptor tyrosine kinases (RTK), PI-3-kinase (PI3K) and mTORC2 activate Akt by phosphorylation on T308 and S473, which, in turn, represses the tuberous sclerosis complex (TSC) by phosphorylating the TSC2 subunit. TSC is a GTPase-activating protein (GAP) that limits the activity of Rheb by promoting Rheb·GDP accumulation, which represses mTORC1. Whereas AMPK and hypoxia stimulate TSC GAP activity to inhibit mTORC1, Receptor Tyrosine Kinase (RTK)–mediated Akt activation inhibits TSC, resulting in mTORC1 activation. Inhibiting TSC allows rheb·GTP accumulation and mTORC1 activation, and results in p70S6K and 4E-BP1 phosphorylation. By stimulating ribosomal protein S6 phosphorylation (rpS6), p70 S6K activation by mTORC1 stimulates the eIF4A-accessory factor eIF4B and inhibits eukaryotic elongation factor 2 (eEF2) kinase, stimulating elongation. Normally, p70 S6K activation represses PI3-kinase (PI3K) to feedback and limit mTORC1 activation. 4E-BP1 hyperphosphorylation (depicted as circled P) relieves translational repression and releases eIF4E.
Figure 3.
Figure 3.
Antagonism of host antiviral defenses that inactivate eIF2 by viral functions. eIF2·GTP forms a ternary complex (TC) with Met-tRNAi and is loaded into the P-site in the 40S ribosome to form a 43S pre-initiation complex (top right). Upon engaging mRNA via other initiation factors (e.g., eIF4F) or via a specialized cis-acting RNA element (e.g., an IRES), the AUG start codon is identified (typically via scanning), the GTPase-activating protein eIF5 stimulates GTP hydrolysis, and 60S subunit joining triggers eIF2·GDP + phosphate (Pi) release. Translation elongation is executed by the resulting 80S ribosome. Inactive eIF2 (α, β, γ subunits depicted in center) bound to GDP (eIF2·GDP) is recycled to the active GTP-bound form (eIF2·GTP) by the five-subunit guanine nucleotide exchange factor eIF2B. Site-specific eIF2 phosphorylation on its α-subunit (S51) by either of four different cellular eIF2α-kinases (see text), each of which is activated by discrete stress, prevents eIF2 recycling. Phosphorylated eIF2 (bottom) binds tightly to and inhibits eIF2B, blocking translation initiation. The host protein phosphatase 1 catalytic (PP1c) subunit can dephosphorylate eIF2 when partnered with either an inducible (GADD34) or constitutively active (CReP) regulatory component. Virus-encoded factors that antagonize (red, to the left) specific host eIF2α kinases are indicated to the left. Viral PKR antagonists have been subdivided according to their mechanisms of action (see text; [dsRNA BPs] double-stranded RNA binding proteins). Virus-encoded factors that activate cellular phosphatases to dephosphorylate eIF2α, or allow translation to proceed without eIF2 or in the presence of phosphorylated eIF2α, are shown (green, to the right).
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