Minding the message: tactics controlling RNA decay, modification, and translation in virus-infected cells

Figure 1.. Viral strategies to oppose and promote mRNA decay. (A) Inhibition of cellular proteins that effect 5′–3′ mRNA decay can be achieved by protection from decapping by cap binding proteins (VPg) and obstruction of the exonuclease Xrn1 by miRNAs and RNA structure (sfRNA). 3′ end decay is similarly opposed by recruitment of viral proteins and formation of RNA structure, and “mixed tailing” can also inhibit poly(A) tail deadenylation by CCR4–NOT. Both 5′ and 3′ targeting cellular mRNA decay proteins may be degraded or relocalized during infection. (B) Viruses inhibit OAS/RNase L and ZAP antiviral cellular RNA decay pathways using diverse strategies. Recognition of dsRNA by OAS is blocked by viral dsRNA-BPs. Viral phosphodiesterases (PDEs) degrade second messenger 2-5A. RNase L activation can also be blocked by viral proteins, up-regulated cellular negative regulator ABCE1, or viral RNA structures. ZAP recognition of virus RNA (vRNA) is evaded by CG suppression, viral ZAP-binding proteins, and ZAP cleavage by virus proteases. (C) Viral proteins stimulate mRNA decay via multiple modalities. They can contain direct enzymatic activity such as mRNA decapping and endonucleolytic cleavage,…

Figure 2.. Controlling cap-dependent 40S ribosome loading in virus-infected cells. Sampling extracellular and intracellular cues (growth factor, nutrients, O2, and energy) allows 40S ribosome loading onto capped mRNAs to be responsive to changing environmental and physiological conditions, including virus infection. Receptor tyrosine kinase (RTK) signaling through PI3-kinase (PI3-K) and PDK1 stimulates Akt phosphorylation (T308 and S473). Once activated, Akt represses the tuberous sclerosis complex (TSC1/2), which results in Rheb-GTP accumulation and mTORC1 activation. Physiological stress (energy, O2, or nutrient insufficiency) prevents mTORC1 activation. The translational repressor 4E-BP1 regulates the availability of the cap-binding protein eIF4E. Hyperphosphorylation and inactivation of 4E-BP1 releases eIF4E, which interacts with eIF4G and the DEAD-box helicase eIF4A to assemble the multisubunit eIF4F complex on m7G-capped mRNA. Regulated eIF4F assembly controls eIF3-bound 40S loading onto capped mRNA. Virus-encoded effectors that stimulate (green) or repress (red) the indicated host factors to control 40S loading and translation initiation are shown. (SV40) Simian virus 40, (calici)…

Figure 3.. Viral strategies to preserve initiator tRNA loading onto 40S subunits. (Left panel) eIF2 is a GTP-binding initiation factor comprised of three subunits (α, β, and γ) that loads eIF3-bound 40S with Met-tRNAi. After recruitment of mRNA containing eIFs and AUG identification, eIF5-dependent GTP hydrolysis is followed by 60S joining and initiation, and subsequent 80S-mediated elongation. The GEF activity of the eIF2B pentamer–dimer recycles inactive eIF2•GDP to the active GTP-bound form. S51 eIF2α phosphorylation precludes initiation by associating with and inhibiting eIF2B, obstructing GDP-GTP exchange. eIF2α phosphorylation is controlled by four eIF2α kinases, each activated by distinct biological stress, and PP1c with its cognate constitutive (CrEP) or inducible (GADD34) regulatory subunit. Virus-encoded functions that antagonize (red) host eIF2α kinases, stimulate PP1, or support translation despite phospho-eIF2 accumulation (green) are indicated. (aa) Amino acid.

Figure 4.. Ribosome proteins (RPs) that regulate translation in virus-infected cells. The figure depicts solvent and intrasubunit surfaces of 40S and 60S subunits with ribosomal RNA (gray) and RPs (tan). Highlighted RPs represent RPs important for virus IRES-mediated translation (green) or proviral functions (pink), or post-translationally modified during viral infection (blue). (Ribosome structure derived from PDB entry 4v88; figure based on data from Ben-Shem et al. [2011]).