Abstract
The emergence and global spread of SARS-CoV-2 has resulted in the urgent need for an in-depth understanding of molecular functions of viral proteins and their interactions with the host proteome. Several individual omics studies have extended our knowledge of COVID-19 pathophysiology1,2,3,4,5,6,7,8,9,10. Integration of such datasets to obtain a holistic view of virus–host interactions and to define the pathogenic properties of SARS-CoV-2 is limited by the heterogeneity of the experimental systems. Here we report a concurrent multi-omics study of SARS-CoV-2 and SARS-CoV. Using state-of-the-art proteomics, we profiled the interactomes of both viruses, as well as their influence on the transcriptome, proteome, ubiquitinome and phosphoproteome of a lung-derived human cell line. Projecting these data onto the global network of cellular interactions revealed crosstalk between the perturbations taking place upon infection with SARS-CoV-2 and SARS-CoV at different levels and enabled identification of distinct and common molecular mechanisms of these closely related coronaviruses. The TGF-β pathway, known for its involvement in tissue fibrosis, was specifically dysregulated by SARS-CoV-2 ORF8 and autophagy was specifically dysregulated by SARS-CoV-2 ORF3. The extensive dataset (available at https://covinet.innatelab.org) highlights many hotspots that could be targeted by existing drugs and may be used to guide rational design of virus- and host-directed therapies, which we exemplify by identifying inhibitors of kinases and matrix metalloproteases with potent antiviral effects against SARS-CoV-2.
【초록키워드】 COVID-19, Transcriptome, SARS-CoV-2, proteomics, Coronaviruses, SARS-CoV, knowledge, fibrosis, drug, molecular mechanism, virus, autophagy, heterogeneity, Antiviral effect, Spread, ORF8, pathway, dataset, proteome, inhibitor, TGF-β, Interaction, integration, Perturbation, ORF3, Viral protein, tissue, phosphoproteome, These data, both viruses, Host-directed therapies, pathogenic, kinase, hotspot, human cell, Host, highlight, to define, dysregulated, cellular interaction, infection with SARS-CoV-2, matrix metalloprotease, molecular function, virus–host interaction, 【제목키워드】 SARS-CoV-2, proteomics, SARS-CoV, Perturbation, Host, reveal,