Canadian Scientists Identify RNA Interference Effector Protein Argonaute 2 As A Powerful Restriction Factor Against SARS-CoV-2
: The battle against the SARS-CoV-2 virus, responsible for the devastating COVID-19 pandemic, has intensified as scientists uncover new insights into the host-virus interactions. A recent groundbreaking study conducted by researchers from the University of Alberta, University of Saskatchewan, and McGill University has revealed the significant role of Argonaute 2 (Ago2), a crucial component of the RNA interference (RNAi) pathway, in restricting the replication of SARS-CoV-2.
The RNAi pathway is a gene-regulatory system found in most eukaryotes, which employs microRNAs (miRNAs) and small interfering RNAs (siRNAs) to target homologous mRNAs. This targeting process leads to the degradation or translational suppression of these mRNAs.
While the RNAi pathway's antiviral defense functions have been well-documented in plants and invertebrates, its role in limiting viral infections in mammalian cells has remained less understood. Till now, there has been no proper studies nor any COVID-19 News
reports with regards to RNAi pathway's antiviral potential in any coronavirus infections let alone about any other viruses in mammals.
The study team conducted meticulous investigations to unravel the involvement of Ago2 in SARS-CoV-2 replication. Through microscopic analyses of infected cells, they observed that a pool of Ago2 closely associates with viral replication sites. To evaluate Ago2's impact on viral replication, they conducted gene ablation studies, which demonstrated that the loss of Ago2 led to a staggering over 1,000-fold increase in peak viral titers. Furthermore, they discovered that the replication of the alphacoronavirus 229E was also significantly heightened in cells lacking Ago2, indicating its broad antiviral activity.
Notably, the antiviral activity of Ago2 was found to be reliant on both its small RNA-binding capacity and its endonuclease function. Intriguingly, the study revealed that the absence of Dicer, an upstream component of the RNAi pathway, did not alter viral replication, suggesting that Ago2's antiviral activity operates independently of Dicer-processed miRNAs.
The study team found several SARS-CoV-2-derived small RNAs that bind to Ago2 through deep sequencing of infected cells, conducted by other research groups. Moreover, they discovered that a mutant virus lacking the most abundant viral miRNA derived from the ORF7A gene exhibited significantly reduced sensitivity to Ago2-mediated restriction.
These study findings, combined with the observation that Ago2's endonuclease and small RNA-binding functions are
essential for its antiviral function, indicate that Ago2-small viral RNA complexes target nascent viral RNA produced at replication sites for cleavage.
Further research is warranted to fully elucidate the mechanism underlying the processing of viral small RNAs used by Ago2 to limit coronavirus replication.
The discovery of Ago2 as a potent restriction factor against SARS-CoV-2 holds great promise for the development of novel antiviral therapeutics. By targeting this specific RNAi effector protein, scientists may be able to devise new strategies to combat viral infections and enhance our preparedness for future pandemics.
The study findings were published in the peer reviewed Journal of Molecular Biology.
Protein argonaute-2 is a protein that in humans is encoded by the EIF2C2 gene.This gene encodes a member of the Argonaute family of proteins which play a role in RNA interference. The encoded protein is highly basic, and contains a PAZ domain and a PIWI domain. It may interact with Dicer1 and play a role in short-interfering-RNA-mediated gene silencing. Ago2 (Argonaute 2, EIF2C2) is the only member in AGO family with catalytic activity and of extreme importance during small RNAs guided gene silencing processes.
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