Coronavirus takeover of host cell translation and intracellular antiviral response: a molecular perspective

Figures

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  Figure 1. Different viral strategies target translation at different steps. Viruses must use cellular machinery to produce their proteins and many strategies to control translation have evolved. Various viral mechanisms inhibit cellular translation steps (indicated with a minus and pink box). On the other hand, viruses can overcome cellular anti-viral immune responses by promoting the translation of their own viral mRNAs through unique strategies (indicated with plus and beige boxes).

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  Figure 2. Life cycle of coronaviruses and implications for translation regulation. Numbers (1–9) indicate life cycle steps of the virus, while interactions with host translation are represented by letters (A–H). Upon binding of a virion to host receptors, membrane fusion releases the positive sense RNA genome into the cytoplasm (1). The genome is translated by the host cell machinery to produce two different polyproteins by programmed ribosomal frameshifting (2 and A). Cleavage of polypeptides (3) produces non-structural proteins (Nsps), including RdRp that synthesize negative and positive sense (−Sense and +Sense) RNAs (4, 5) inside of double-membrane vesicles (DMV) that act as platforms for viral replication. Nsp1 binds to ribosomes (B), inhibits host mRNA translation and stimulates host mRNA degradation (C). Viral RNAs are polyadenylated, and when their concentration is increased, they compete to bind Poly(A)-binding proteins (PABP) (D). RNA editing (E) may introduce variable sequences in the viral progeny and alter the translation and stability properties of the viral RNAs. The subgenomic RNAs are translated to synthesize structural and accessory proteins (6 and F) that can stimulate…

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  Figure 3. Nsp1 inhibits translation by binding to the mRNA channel (through its CTD) and the A-site of the 40S (through its NTD). The CTD binds with high affinity to the mRNA entry channel, where it anchors Nsp1 to the ribosome and would sterically clash with mRNA accommodation. The NTD dynamically interacts with the decoding center (ribosomal A-site), further contributes to translation inhibition, and plays a role in the selective translation of viral mRNAs.

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  Figure 4. Features of coronaviruses to hijack and regulate translation in host cells. In −1 programmed ribosomal frameshifting (upper right box), the ribosome encounters a frameshifting site, upon which the ribosome shifts its frame towards −1 within the slippery site. This is caused by the pseudoknot that resides at the mRNA entry channel (PDB: 7O7Z). Upon infection, translation is inhibited by Nsp1 through binding to the 40S subunit. Viral mRNAs harboring the first stem-loop (SL1) in their 5΄ UTR (upper left box) evade Nsp1-mediated inhibition. The mRNA secondary structure of the 5΄ UTR is based on Wacker et al (2020) and Miao et al (2021) and the mRNA pseudoknot on Bhatt et al (2021).