Importin-5 functions as a chaperone for viral glycoproteins to promote virus budding.
Description
Thousands of people are affected by arenavirus infections annually and no specific and safe antiviral therapy for arenaviruses are available. Thus, there is an urgent need to develop effective vaccines or therapeutic strategies to combat arenavirus infections. This task is hampered owing to limited understanding of the molecular details of virus-host interactions. Here, we performed affinity tag-purification mass spectrometry to generate a protein-protein interaction (PPI) map between host cells and arenavirus lymphocytic choriomeningitis virus (LCMV) proteins. We uncovered 299 high-confidence LCMV-host PPIs, including one between the LCMV glycoprotein and host karyopherin importin-5 (IPO5). We further showed that the C-terminus cytosol tail of the viral glycoprotein enriched in basic amino acids, directly interacts with IPO5. IPO5 acts as a chaperone to facilitate the transport and translocation of glycoproteins to the host cell membrane surface, thereby promoting viral budding. On this basis, a highly attenuated LCMV mutant (LCMV-EED) was generated, which protected mice from the lethal challenge of LCMV. Notably, we found that several enveloped RNA viruses also possess similar C-termini cytosol tails that contain basic amino acids of glycoproteins, which plays an important role in the effect of IPO5 on viral budding. Thus, the C-terminus of glycoproteins can serve as a novel broad-spectrum target for the development of vaccines and antivirals.