Targeting G9a translational mechanism of SARS-CoV-2 pathogenesis for multifaceted therapeutics of COVID-19 and its sequalae

Muneer, A.; Xie, L.; Xie, X.; Zhang, F.; Wrobel, J.; Yan, X.; Yu, X.; Wang, C.; Gheorghe, C.; Wu, P.; Song, J.; Ming, G.-L.; Jin, J.; Song, H.; Shi, P.-Y.; Chen, X.

doi:10.1101/2024.03.04.583415

bioRxiv · 10.1101/2024.03.04.583415

Targeting G9a translational mechanism of SARS-CoV-2 pathogenesis for multifaceted therapeutics of COVID-19 and its sequalae

Muneer, A.·Xie, L.·Xie, X.·Zhang, F.·Wrobel, J.·Yan, X.·Yu, X.·Wang, C.·Gheorghe, C.·Wu, P.·Song, J.·Ming, G.-L.·Jin, J.·Song, H.·Shi, P.-Y.·Chen, X.

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Abstract

By largely unknown mechanism(s), SARS-CoV-2 hijacks the host translation apparatus to promote COVID-19 pathogenesis. We report that the histone methyltransferase G9a noncanonically regulates viral hijacking of the translation machinery to bring about COVID-19 symptoms of hyperinflammation, lymphopenia, and blood coagulation. Chemoproteomic analysis of COVID-19 patient peripheral mononuclear blood cells (PBMC) identified enhanced interactions between SARS-CoV-2-upregulated G9a and distinct translation regulators, particularly the N6-methyladenosine (m6A) RNA methylase METTL3. These interactions with translation regulators implicated G9a in translational regulation of COVID-19. Inhibition of G9a activity suppressed SARS-CoV-2 replication in human alveolar epithelial cells. Accordingly, multi-omics analysis of the same alveolar cells identified SARS-CoV-2-induced changes at the transcriptional, m6A-epitranscriptional, translational, and post-translational (phosphorylation or secretion) levels that were reversed by inhibitor treatment. As suggested by the aforesaid chemoproteomic analysis, these multi-omics-correlated changes revealed a G9a-regulated translational mechanism of COVID-19 pathogenesis in which G9a directs translation of viral and host proteins associated with SARS-CoV-2 replication and with dysregulation of host response. Comparison of proteomic analyses of G9a inhibitor-treated, SARS-CoV-2 infected cells, or ex vivo culture of patient PBMCs, with COVID-19 patient data revealed that G9a inhibition reversed the patient proteomic landscape that correlated with COVID-19 pathology/symptoms. These data also indicated that the G9a-regulated, inhibitor-reversed, translational mechanism outperformed G9a-transcriptional suppression to ultimately determine COVID-19 pathogenesis and to define the inhibitor action, from which biomarkers of serve symptom vulnerability were mechanistically derived. This cell line-to-patient conservation of G9a-translated, COVID-19 proteome suggests that G9a inhibitors can be used to treat patients with COVID-19, particularly patients with long-lasting COVID-19 sequelae.

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Muneer, A., Xie, L., Xie, X., Zhang, F., Wrobel, J., Yan, X., Yu, X., Wang, C., Gheorghe, C., Wu, P., Song, J., Ming, G.-L., Jin, J., Song, H., Shi, P.-Y., Chen, X.. 2024-03-06. Targeting G9a translational mechanism of SARS-CoV-2 pathogenesis for multifaceted therapeutics of COVID-19 and its sequalae. https://doi.org/10.1101/2024.03.04.583415

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