Cell
The Global Phosphorylation Landscape of SARS-CoV-2 Infection
Jun 29, 2020SUMMARY
The causative agent of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected millions and killed hundreds of thousands of people worldwide, highlighting an urgent need to develop antiviral therapies. Here, we present a quantitative mass spectrometry-based phosphoproteomics survey of SARS-CoV-2 infection in Vero E6 cells, revealing dramatic rewiring of phosphorylation on host and viral proteins. SARS-CoV-2 infection promoted casein kinase II (CK2) and p38 MAP kinase activation, production of diverse cytokines, and shutdown of mitotic kinases resulting in cell cycle arrest. Infection also stimulated a marked induction of CK2-containing filopodia protrusions possessing budding viral particles. Eighty-seven drugs and compounds were identified by mapping global phosphorylation profiles to dysregulated kinases and pathways. We found pharmacologic inhibition of p38, CK2, CDKs, AXL and PIKFYVE kinases to possess antiviral efficacy, representing potential COVID-19 therapies….
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Silmitasertib, an inhibitor of CSNK2A1 and CSNK2A2, was found to possess antiviral activity (IC50 = 2.34 μM; Figure 7C, S5). In conjunction with data supporting physical interaction (Gordon et al. 2020) and co-localization with N protein (Figure 5F), as well as a potential role in remodeling extracellular matrix upon infection (Figure 5, S3), CK2 signaling appears to be an important pathway hijacked by SARS-CoV-2. Furthermore, silmitasertib is currently being considered for human testing as a potential treatment for COVID-19.
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As a positive control and for comparison, remdesivir was tested and the expected favorable antiviral activity was observed (IC50 = 1.28 µM; Figure 7B). Silmitasertib, an inhibitor of CSNK2A1 and CSNK2A2, was found to possess antiviral activity (IC50 = 2.34 µM; Figure 7C, S5). In conjunction with data supporting physical interaction (Gordon et al. 2020) and co-localization with N protein (Figure 5F), as well as a potential role in remodeling extracellular matrix upon infection (Figure 5, S3), CK2 signaling appears to be an important pathway hijacked by SARS-CoV-2. Furthermore, silmitasertib is currently being considered for human testing as a potential treatment for COVID-19.
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Furthermore, CK2 was found to regulate actin tail formation during vaccinia virus infection, enabling efficient cell-to-cell spread of the virus (D. E. Alvarez and Agaisse 2012; Smith and Law 2004). Here, the CK2 inhibitor silmitasertib displayed robust antiviral activity, suggesting a role for this kinase in regulating the SARS-CoV-2 life cycle.
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Silmitasertib, a small molecule undergoing clinical trials for various cancers, is now being considered for testing in humans to combat COVID-19. Although the effectiveness of CK2 inhibition may be attributed to its regulation of stress granules (Gordon et al. 2020), viral egress and dissemination could be facilitated by CK2-mediated remodeling of the extracellular matrix (Figure 5).
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Here, the CK2 inhibitor silmitasertib displayed robust antiviral activity, suggesting a role for this kinase in regulating the SARS-CoV-2 life cycle.
Highlights ● Phosphoproteomics analysis of SARS-CoV2 infected cells uncovers signaling rewiring ● Infection promotes host p38 MAP kinase cascade activity and shutdown of mitotic kinases ● Infection stimulates CK2-containing filopodia protrusions with budding virus ● Kinase activity analysis identifies potent antiviral drugs and compounds
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https://www.cell.com/cell/fulltext/S0092-8674(20)30811-4