To translate, or not to translate: viral and host mRNA regulation by interferon-stimulated genes

Abstract

Type I interferon (IFN) is one of the first lines of cellular defense against viral pathogens. As a result of IFN signaling, a wide array of IFN-stimulated gene (ISG) products is upregulated to target different stages of the viral life cycle. We review recent findings implicating a subset of ISGs in translational regulation of viral and host mRNAs. Translation inhibition is mediated either by binding to viral RNA or by disrupting physiological interactions or levels of the translation complex components. In addition, many of these ISGs localize to translationally silent cytoplasmic granules, such as stress granules and processing bodies, and intersect with the microRNA (miRNA)-mediated silencing pathway to regulate translation of cellular mRNAs.

Keywords: microRNA function; microRNA processing; translational regulation.

Figure 1

Interferon-stimulated genes (ISGs) repress translation by targeting host and viral factors important for regulation of translation initiation and elongation. Translation initiation involves binding of eukaryotic initiation factor (eIF) 4E to the m7G cap structure at the 5′ end of mRNAs (middle top). Both eIF4E and poly(A)-binding protein (PABP) interact with the scaffold protein eIF4G, leading to mRNA circularization. The 43S preinitiation complex, which consists of the eIF3 complex (13 subunits; a–m), the ternary complex eIF2-GTP-Met-tRNAⁱ and the 40S ribosomal subunit, is then recruited (top left). The 43S complex scans the 5′ untranslated region (UTR) of the mRNA, which is unwound by the RNA helicase eIF4A until the initiating AUG is found. As a result, the 60S ribosomal subunit joins the 40S ribosomal subunit to form the 80S ribosome, resulting in translation initiation and elongation, and formation of polyribosomes (polysomes) on the mRNA (middle bottom). The ISGs that target some of the translation initiation and elongation steps are depicted in red.

Figure I

Enzymes responsible for addition and removal of ADP-ribose.

Figure 2

Interferon-stimulated genes (ISGs) localize to stress granules (SGs) and P bodies (PBs), translationally silent sites in the cytoplasm. Polysomes can be dissociated by signals of translational silencing or deadenylation, and the actively translating mRNA is redirected to SGs and PBs for repression or triage. Messenger ribonucleoproteins can also move from one type of granule to the other. ISGs that are localized to SGs upon stress induction and to PBs are shown as stars.

Figure 3

Interferon-stimulated genes (ISGs) affect microRNA (miRNA) processing, production, and actions. The mammalian RNAi pathway is depicted here. The RNase III enzyme Drosha first processes longer primary miRNA (pri-miRNA) transcripts into pre-miRNA hairpins in the nucleus. After nuclear export, pre-miRNAs are cleaved into miRNA duplexes by Dicer in the cytoplasm and loaded onto Argonaute 2 (Ago2). The minimal RNA-induced silencing complex (RISC) complex (Dicer-TRBP-Ago2) targets transcripts with extensive or perfect sequence complementarity to the miRNA leading to mRNA cleavage, whereas imperfect sequence complementarity between the target transcript and miRNA leads to translational silencing, deadenylation, and mRNA degradation. ISGs interacting with different components of the RNAi pathway are shown as stars. A-to-I editing by adenosine deaminase acting on RNA 1 (ADAR1) either leads to (A) decreased processing and increased degradation of pri-miRNA , or (B) silencing of a different set of gene targets . The involvement of Moloney leukemia virus type 10 homolog (MOV10) in different repressive mechanisms of miRNA is controversial and therefore highlighted by question marks.