Abstract
The rapidly and constantly evolving coronavirus, SARS-CoV-2, imposes a great threat to human health causing severe lung disease and significant mortality. Cytoplasmic stress granules (SGs) exert anti-viral activities due to their involvement in translation inhibition and innate immune signaling. SARS-CoV-2 sequesters important SG nucleator proteins and impairs SG formation, thus evading the host response for efficient viral replication. However, the significance of SGs in COVID-19 infection remains elusive. In this study, we utilize a protein-protein interaction network approach to systematically dissect the crosstalk of human post-translational regulatory networks governed by SG proteins due to SARS-CoV-2 infection. We uncovered that 116 human SG proteins directly interact with SARS-CoV-2 proteins and are involved in 430 different brain disorders including COVID-19. Further, we performed gene set enrichment analysis to identify the drugs against three important key SG proteins (DYNC1H1, DCTN1, and LMNA) and also looked for potential microRNAs (miRNAs) targeting these proteins. We identified bexarotene as a potential drug molecule and miRNAs, hsa-miR-615-3p, hsa-miR-221-3p, and hsa-miR-124-3p as potential candidates for the treatment of COVID-19 and associated manifestations.
Highlights
The causative agent of COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an enveloped, single-stranded ~30 kb RNA virus of the family Coronaviridae [1]
In the early phase of many viral infections, the presence of viral genomic RNAs activates protein kinase R (PKR), resulting in eIF2α phosphorylation, mRNA translation inhibition, and the formation of stress granules (SGs) enriched with translation initiation factors such as eIF3b
A total of 116 SG proteins showing interaction with SARS-CoV-2 proteins were identified by comparing the two lists (Figure 1A). We found that these 116 proteins interact with 22 SARS-CoV-2 proteins with the highest number of interactions to ORF6 (14), N and NSP6 (13), NSP12, and NSP13 (11), ORF7 (10), and NSP7 (7) protein (Figure 1B)
Summary
The causative agent of COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an enveloped, single-stranded ~30 kb RNA virus of the family Coronaviridae [1]. Dysregulation of SG formation and disassembly is involved in viral infection, cancer, and neurodegeneration [13,14,15,16] Coronaviruses such as mouse hepatitis coronavirus and transmissible gastroenteritis virus were shown to induce SG assembly [17]. Several SARS-CoV-2 human interactomes have been created which aid in comprehending the viral entry, infection, and disease development mechanisms [23,24,26,27]. Analysis of these networks has revealed commonalities and distinctions based on genes and molecular pathways associated with viral pathogenicity. The gene set enrichment analysis (GSEA) was studied for the identification of drugs affecting the gene expression of selected SG genes
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