Host translation at the nexus of infection and immunity

Abstract

By controlling gene expression at the level of mRNA translation, organisms temporally and spatially respond swiftly to an ever-changing array of environmental conditions. This capacity for rapid response is ideally suited for mobilizing host defenses and coordinating innate responses to infection. Not surprisingly, a growing list of pathogenic microbes target host mRNA translation for inhibition. Infection with bacteria, protozoa, viruses, and fungi has the capacity to interfere with ongoing host protein synthesis and thereby trigger and/or suppress powerful innate responses. This review discusses how diverse pathogens manipulate the host translation machinery and the impact of these interactions on infection biology and the immune response.

Figure 1

Translation Initiation and Elongation in Eukaryotes Initiation and elongation steps each require discrete translation factors. (A) Initiation. Formation of the 43S preinitiation complex involves loading the initiator-methionine tRNA (Met-tRNA_i) into the ribosomal P site as a complex with eIF2·GTP. The 40S subunit is also associated with eIF1 (blue triangle, 1), eIF1A (blue triangle, 1A), eIF3, and eIF5. The 43S complex is next positioned onto the 5′ end of a capped (orange circle, m⁷G), polyadenylated mRNA by eIF4F, a three-subunit complex composed of the cap-binding protein eIF4E, eIF4G, and eIF4A (shown as 4E, 4G, and 4A). Poly(A)-binding protein (PABP) bound to the polyadenylated 3′ mRNA also associates with eIF4G bound to the 5′ end. This forms a “closed-loop” topology, linking 5′ and 3′ mRNA ends. The eIF4E kinase Mnk is shown associated with eIF4G where it phosphorylates eIF4E (circle, P). The mRNA-bound 48S complex scans the mRNA to locate the AUG start codon, whose recognition is facilitated by eIF3, eIF1, and 1A. Initiation factor release follows 60S subunit joining, which requires eIF5B. (B) Elongation. Loading of a charged tRNA into the 80S ribosome A site requires eEF1A·GTP. Ribosome-catalyzed peptide bond formation ensues. 80S translocation requires eukaryotic elongation factor 2 (eEF2), which moves the deacetylated tRNA to the E site, positioned the peptidyl-tRNA in the P site and re-exposes the A site.

Figure 2

Integration of Signals by mTORC1 Controls Cap-Dependent Translation Availability of growth factors (receptor tyrosine kinase [RTK] signaling), oxygen, glucose, and energy regulate the GTPase activating protein TSC (composed of subunits hamartin [TSC1] and tuberin [TSC2]), which represses mTOR complex 1 (mTORC1) by promoting Rheb·GDP accumulation. Amino acid availability controls mTORC1 through the Rag GTPases. Inhibition of TSC allows Rheb·GTP accumulation and mTORC1 activation and results in p70 ribosomal protein S6 kinase (p70 S6K) and 4E-BP1 phosphorylation. 4E-BP1 hyperphosphorylation relieves translational repression and releases eIF4E (labeled 4E), allowing eIF4E to bind eIF4G (labeled 4G) and assemble the heterotrimer subunit initiation factor eIF4F (composed of eIF4E, eIF4A [labeled 4A], and eIF4G) on 7-methylguanosine (m⁷G; orange circle)-capped mRNA (see Figure 1A). Poly(A)-binding protein (PABP) is depicted bound to the 3′ poly(A) tail and also associates with eIF4G to stimulate translation. For simplicity, only eIF3, but not other 43S complex components (eIF1, eIF1A, eIF2, eIF5, and Met-tRNAi as shown in Figure 1), is depicted. In addition to stimulating ribosomal protein S6 (RPS6) phosphorylation, p70 S6K activation by mTORC1 stimulates the eIF4A accessory factor eIF4B, relieves PDCD4-mediated repression of eIF4A, and inhibits eukaryotic elongation factor 2 (eEF2) kinase to stimulate elongation. Pathogen strategies for activating and inhibiting steps within this pathway to control host translation are indicated in red; see the main text for details. IFN, interferon; HVs, herpesviruses; VV, vaccinia virus; PVs, picornaviruses (poliovirus, EMCV, rhinovirus); SARS coV, SARS coronavirus; IAV, influenza A virus; γHVs, gamma herpesviruses (EBV, KSHV, MHV68).

Figure 3

Control of Translation Initiation by eIF2 and Host Regulatory Kinases that Phosphorylate Its α subunit A ternary complex, comprised of eIF2 (α, β, and γ subunits, depicted) and GTP bound to the initiator-methionine tRNA (Met-tRNA_i), loads Met-tRNA_i into the ribosomal P site and forms a 43S preinitiation complex. After recruitment of eIF4F- and poly(A)-binding protein (PABP)-bound mRNA and recognition of the AUG start codon by scanning ribosomes, the GTPase-activating protein eIF5 stimulates GTP hydrolysis, and 60S subunit joining triggers the release of eIF2·GDP and inorganic phosphate (P_i). The resulting 80S ribosome carries out the elongation phase (Figure 1B). Inactive, GDP-bound eIF2 (eIF2·GDP) is recycled to the active GTP-bound form by the five-subunit guanine nucleotide exchange factor eIF2B. Four different cellular eIF2α kinases (described in the main text), each of which is activated by a discrete stress, phosphorylate eIF2α, and prevent eIF2 recycling. Phosphorylated eIF2 binds tightly to and inhibits eIF2B, blocking canonical tRNA^met-initiated translation. When bound to either the inducible (growth arrest and DNA damage-inducible protein 34 [GADD34]) or constitutively active (CReP) regulatory subunit, the host protein phosphatase 1 catalytic (PP1c) subunit dephosphorylates eIF2. Pathogens shown in red and the different eIF2α kinases they activate are indicated. Viral (CrPV and other IRESs, Sindbis 26S mRNA) and host (uORF-containing, eIF2D-dependent, tRNA^leu-initiated) mRNAs that are translated in the presence of phosphorylated eIF2 are indicated. SinV, Sindbis virus; VSV, vesicular stomatitis virus; Ad, adenovirus; CrPV, cricket paralysis virus; uORF, upstream open reading frame; aa, amino acid.