Move and countermove: the integrated stress response in picorna- and coronavirus-infected cells

Abstract

Viruses, when entering their host cells, are met by a fierce intracellular immune defense. One prominent antiviral pathway is the integrated stress response (ISR). Upon activation of the ISR - typically though not exclusively upon detection of dsRNA - translation-initiation factor eukaryotic initiation factor 2 (eIF2) becomes phosphorylated to act as an inhibitor of guanine nucleotide-exchange factor eIF2B. Thus, with the production of ternary complex blocked, a global translational arrest ensues. Successful virus replication hinges on effective countermeasures. Here, we review ISR antagonists and antagonistic mechanisms employed by picorna- and coronaviruses. Special attention will be given to a recently discovered class of viral antagonists that inhibit the ISR by targeting eIF2B, thereby allowing unabated translation initiation even at exceedingly high levels of phosphorylated eIF2.

Figure 1

Schematic representation of integrated stress response and different classes of viral antagonists. Canonical translation initiation critically requires eIF2–GTP–Met–tRNAi TCs. The formation of TCs requires the activity of the guanine nucleotide-exchange factor eIF2B, which catalyzes the nucleotide exchange of eIF2–GDP into its active form eIF2–GTP. The integrated stress response is constituted by a set of four kinases, which, in response to a range of stimuli, phosphorylates eIF2α. Phosphorylated eIF2 is as a competitive inhibitor of eIF2B, thereby downregulating TC formation resulting in translational inhibition. The buildup of inactive mRNA-ribosome complexes finally culminates in the formation of SGs. Viruses have evolved a wide range of antagonists and antagonistic mechanisms to counteract the ISR at different levels. These can be assigned to specific classes based on their mechanism of action.

Figure 2

Genome organization of picornaviruses and coronaviruses. Schematic overview of genome structure and organization of picornaviruses (a), where we took EMCV as an example, and coronaviruses (b), where we took the SARS-CoV-2 genome as an example. (*) represents the C-terminal N peptide generated from an internal TRS.

Figure 3

Complex of eIF2B with eIF2, eIF2(p), and SFSV NSs. (a) Cryo-EM structure of eIF2B in active conformation complexed with eIF2 (N-terminal domain of eIF2α shown exclusively) and NSs (PDB: 7F67). eIF2B subunits shown in surface representation (α, pale green; β, light blue; γ, blue white; δ, light pink; ε, wheat) and with NSs (yellow) and eIF2α (res. 3–185, red) in cartoon presentation. (b) eIF2B in inactive conformation complexed with the eIF2α(P) N-terminal domain as in (a) (PDB: 6O9Z). (c) Close-up of the eIF2(p)-binding site (PDB: 6O9Z). eIF2α(P) (res. 5–180) in red, eIF2B α- and δ-subunits, shown in pale green and light pink, respectively. Cartoon representation. (d) Close-up of the NS-binding site as above. NSs in yellow (PDB: 7RLO).