The ribosome strikes back: monitoring and perturbing co-translational processes to combat viral infection

Pathogenic viruses continue to pose a major threat to public health worldwide, with prophylactic and therapeutic options still lacking for many life-threatening infections. One emerging antiviral approach targets cellular proteostasis factors, exploiting the hyper-dependence of viruses on specific nodes of the protein synthesis and folding network. To better define how viruses interact with and hijack this network, we used mass-spectrometry to monitor changes in the composition of ribosomes during infection with three human viruses—zika, dengue and polio. We find that all three induce extensive remodeling of the protein synthesis apparatus, with hundreds of RNA- and nascent chain-binding factors either recruited to or displaced from ribosomes translating viral genomes. These include specialized translation factors, innate immune sensors, molecular chaperones and modifying enzymes. We show that, through such changes, viruses not only evade immune detection and RNA degradation, but also facilitate ribosome scanning, translation elongation, and folding of viral nascent chains. We further demonstrate that host factors involved in these co-translational processes can be targeted, with minimal toxicity, to reduce viral proliferation. Our proteomic strategy offers a novel ribosome-centric perspective on virus-host interactions and helps identify mechanistic aspects of infection that are particularly susceptible to antiviral intervention.