Journal
ANTIVIRAL RESEARCH
Volume 190, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.antiviral.2021.105064
Keywords
Antiviral drugs; COVID-19; Proteomics; Stress granules; DEAD RNA helicase; G3BP1
Categories
Funding
- Ministry of Health [COVID-2020-12371817]
- Avvocati e Procuratori dello Stato, AIRC [17404, IG2018-21880]
- Beyond Borders University of Rome Tor Vergata
- Regione Lazio (Gruppi di ricerca) [E56C18000460002]
- European Commission - Horizon 2020 (European Virus Archive GLOBAL) [871029]
- European Commission - Horizon 2020 (EU) [101003551]
- Russian Government [14. W03.31.0029]
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The study characterized the interaction between host proteins and SARS-CoV-2 Nucleoprotein in infected cells, identifying key proteins involved in RNA metabolism and translation. It revealed the virus's manipulation of stress granule machinery for replication.
COVID-19 is currently a highly pressing health threat and therapeutic strategies to mitigate the infection impact are urgently needed. Characterization of the SARS-CoV-2 interactome in infected cells may represent a powerful tool to identify cellular proteins hijacked by viruses for their life cycle and develop host-oriented antiviral therapeutics. Here we report the proteomic characterization of host proteins interacting with SARS-CoV-2 Nucleoprotein in infected Vero E6 cells. We identified 24 high-confidence proteins mainly playing a role in RNA metabolism and translation, including RNA helicases and scaffold proteins involved in the formation of stress granules, cytoplasmic aggregates of messenger ribonucleoproteins that accumulate as a result of stress-induced translation arrest. Analysis of stress granules upon SARS-CoV-2 infection showed that these structures are not induced in infected cells, neither eIF2 alpha phosphorylation, an upstream event leading to stress-induced translation inhibition. Notably, we found that G3BP1, a stress granule component that associates with the Nucleoprotein, is required for efficient SARS-CoV-2 replication. Moreover, we showed that the Nucleoprotein-interacting RNA helicase DDX3X colocalizes with viral RNA foci and its inhibition by small molecules or small interfering RNAs significantly reduces viral replication. Altogether, these results indicate that SARS-CoV-2 subverts the stress granule machinery and exploits G3BP1 and DDX3X for its replication cycle, offering groundwork for future development of host-directed therapies.
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