SARS-CoV-2 infections are rapidly spreading around the globe. The rapid development of therapies is of major importance. However, our lack of understanding of the molecular processes and host cell signaling events underlying SARS-CoV-2 infection hinders therapy development. We use a SARS-CoV-2 infection system in permissible human cells to study signaling changes by phosphoproteomics. We identify viral protein phosphorylation and define phosphorylation-driven host cell signaling changes upon infection. Growth factor receptor (GFR) signaling and downstream pathways are activated. Drug-protein network analyses revealed GFR signaling as key pathways targetable by approved drugs. The inhibition of GFR downstream signaling by five compounds prevents SARS-CoV-2 replication in cells, assessed by cytopathic effect, viral dsRNA production, and viral RNA release into the supernatant. This study describes host cell signaling events upon SARS-CoV-2 infection and reveals GFR signaling as a central pathway essential for SARS-CoV-2 replication. It provides novel strategies for COVID-19 treatment. Graphical Abstract Highlights • Phosphoproteomics of SARS-CoV-2-infected cells reveal the signaling landscape • SARS-CoV-2 proteins are extensively phosphorylated in host cells • Infection leads to the activation of growth factor receptor signaling • Drugs inhibiting growth factor receptor signaling prevent viral replication In this study, Klann et al. dissected the host cell signaling landscape upon infection with SARS-CoV-2. Mapping differential signaling networks identified a number of pathways activated during infection. Drug-target network analysis revealed potential therapeutic targets. Growth factor receptor signaling was highly activated upon infection and its inhibition prevented SARS-CoV-2 replication in cells.
【저자키워드】 COVID-19, Drug repurposing, SARS-CoV-2, proteomics, RAS, viral replication, Phosphoproteomics, Signaling, PI3K, TMT,