SARS-CoV-2 hijacks p38β/MAPK11 to promote viral protein translation

Higgins, C. A.; Nilsson-Payant, B. E.; Kurland, A.; Adhikary, P.; Golynker, I.; Danziger, O.; Panis, M.; Rosenberg, B. R.; tenOever, B. R.; Johnson, J. R.

doi:10.1101/2021.08.20.457146

bioRxiv · 10.1101/2021.08.20.457146

SARS-CoV-2 hijacks p38β/MAPK11 to promote viral protein translation

Higgins, C. A.·Nilsson-Payant, B. E.·Kurland, A.·Adhikary, P.·Golynker, I.·Danziger, O.·Panis, M.·Rosenberg, B. R.·tenOever, B. R.·Johnson, J. R.

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Abstract

SARS-CoV-2, the causative agent of the COVID-19 pandemic, drastically modifies infected cells in an effort to optimize virus replication. Included is the activation of the host p38 mitogen-activated protein kinase (MAPK) pathway, which plays a major role in inflammation and is a central driver of COVID-19 clinical presentations. Inhibition of p38/MAPK activity in SARS-CoV-2-infected cells reduces both cytokine production and viral replication. Here, we combined genetic screening with quantitative phosphoproteomics to better understand interactions between the p38/MAPK pathway and SARS-CoV-2. We found that several components of the p38/MAPK pathway impacted SARS-CoV-2 replication and that p38{beta} is a critical host factor for virus replication, and it prevents activation of the type-I interferon pathway. Quantitative phosphoproteomics uncovered several SARS-CoV-2 nucleocapsid phosphorylation sites near the N-terminus that were sensitive to p38 inhibition. Similar to p38{beta} depletion, mutation of these nucleocapsid residues was associated with reduced virus replication and increased activation of type-I interferon signaling. Taken together, this study reveals a unique proviral function for p38{beta} that is not shared with p38 and supports exploring p38{beta} inhibitor development as a strategy towards developing a new class of COVID-19 therapies. ImportanceSARS-CoV-2 is the causative agent of the COVID-19 pandemic that has claimed millions of lives since its emergence in 2019. SARS-CoV-2 infection of human cells requires the activity of several cellular pathways for successful replication. One such pathway, the p38 mitogen-activated protein kinase (MAPK) pathway, is required for virus replication and disease pathogenesis. Here, we applied systems biology approaches to understand how MAPK pathways benefit SARS-CoV-2 replication to inform the development of novel COVID-19 drug therapies.

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Higgins, C. A., Nilsson-Payant, B. E., Kurland, A., Adhikary, P., Golynker, I., Danziger, O., Panis, M., Rosenberg, B. R., tenOever, B. R., Johnson, J. R.. 2021-08-20. SARS-CoV-2 hijacks p38β/MAPK11 to promote viral protein translation. https://doi.org/10.1101/2021.08.20.457146

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