SARS-CoV-2 Infection of Lung Epithelia Leads to an Increase in the Cleavage and Translocation of RNase-III Drosha; Loss of Drosha Is Associated with a Decrease in Viral Replication
Michael T Winters, Emily S Westemeier-Rice, Travis W Rawson, Kiran J Patel, Gabriel M Sankey, Maya Dixon-Gross, Olivia R Mchugh, Nasrin Hashemipour, Mckenna L Carroll, Isabella R Wilkerson, Ivan Martinez
Genes, doi:10.3390/genes16101239
Background/Objectives: Since its emergence, COVID-19-caused by the novel coronavirus SARS-CoV-2-has affected millions globally and led to over 1.2 million deaths in the United States alone. This global impact, coupled with the emergence of five new human coronaviruses over the past two decades, underscores the urgency of understanding its pathogenic mechanisms at the molecular level-not only for managing the current pandemic but also preparing for future outbreaks. Small non-coding RNAs (sncRNAs) critically regulate host and viral gene expression, including antiviral responses. Among the molecular regulators implicated in antiviral defense, the microRNA-processing enzyme Drosha has emerged as a particularly intriguing factor. In addition to its canonical role, Drosha also exerts a non-canonical, interferon-independent antiviral function against several RNA viruses. Methods: To investigate this, we employed q/RT-PCR, Western blot, and immunocytochemistry/immunofluorescence in an immortalized normal human lung/bronchial epithelial cell line (NuLi-1), as well as a human colorectal carcinoma Drosha CRISPR knockout cell line. Results: In this study, we observed a striking shift in Drosha isoform expression following infection with multiple SARS-CoV-2 variants. This shift was absent following treatment with the viral mimetic poly (I:C) or infection with other RNA viruses, including the non-severe coronaviruses HCoV-OC43 and HCoV-229E. We also identified a distinct alteration in Drosha's cellular localization post SARS-CoV-2 infection. Moreover, Drosha ablation led to reduced expression of SARS-CoV-2 genomic and sub-genomic targets. Conclusions: Together, these observations not only elucidate a novel aspect of Drosha's antiviral role but also advance our understanding of SARS-CoV-2 host-pathogen interactions, highlighting potential therapeutic avenues for future human coronavirus infections.
Supplementary Materials: The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/genes16101239/s1 , Figure S1 : The expression of key proteins within the miRNA biogenesis pathway, at the mRNA and protein level, following SARS-CoV-2 infection. (A) Western Blot of four proteins within the miRNA biogenesis pathway in mock and SARS-CoV-2-infected (MOI 1.0) NuLi-1 cells. Dicer expression is significantly decreased following infection. (B) qRT-PCR of the mRNA transcripts of four key proteins within the miRNA biogenesis pathway. Following infection there is no significant change in expression at the transcript level. Data are normalized to Beta-Actin or GAPDH and are presented as mean fold change ± SD from at least three independent experiments. The statistical significance between groups was determined using a two-tailed students T test, or two-way ANOVA followed by Tukey's post hoc test (ns, not significant; * p < 0.05); Figure S2 . siRNA knockdown confirmation of Drosha p140 and p25 isoforms. (A) Western blot validation of Drosha isoforms by siRNA knockdown. NuLi-1 cells were transfected with 100 pmol Drosha-specific siRNA (siDrosha) or a non-targeting control siRNA (siControl). Western blotting shows a marked reduction in both FL and cleavage product (P140 and P25) bands in siDrosha-treated cells, confirming their identity as Drosha-specific. (B) qRT-PCR quantification showed a significant reduction in Drosha mRNA expression. Data..
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