RNA-Silencing Protein AGO4 Functions In Antiviral Defense

Argonaute (AGO) proteins bind to short interfering RNAs (siRNAs) or microRNAs (miRNAs) and form the core of the RNA-induced silencing complex (RISC). Although the function of the AGO proteins in effecting gene silencing is well known, the individual functions of the four members, AGO1-AGO4 in antiviral immunity has remained elusive. A new study published recently reports the novel role of AGO4 protein in the antiviral defense pathway in mammals. This discovery offers a potential “universal” drug target for antiviral treatments in the future.

RNA interference provides innate immunity against invading viruses in plants and invertebrates. In mammals, viral RNAs have been found to elicit interferon (IFN) response following their recognition by specialized receptors. The presence of antiviral RNAi pathways in mammals was a topic of debate until two seminal Science papers published in 2013 had confirmed its existence. Since then, researchers have investigated how these antiviral systems complement or cooperate with each other. In mammals, AGO2 is the catalytically active endonuclease that is essential for processing small RNAs. The other AGO proteins, AGO1, 3 and 4 are thought to be redundant and the knowledge about their other functions is lacking.

Now, a collaborative study headed by the research group of Dr. Kate L. Jeffrey from Massachusetts General Hospital has discovered that AGO4 is essential for antiviral defense. Following up on an earlier study that implicated AGO2 in defending against influenza and other viruses in mammals in an IFN independent-manner, the authors had set out to investigate the antiviral functions of the other three members.

AGO4 was found to be abundant in the IFN-producing innate immune cells such as macrophages, monocytes, dendritic cells, and granulocytes than other counterparts. By promoting IFN after infection, AGO4 performed antiviral defense activity, especially against some RNA viruses in an IFN-dependent manner. Its absence from specific immune cells resulted in hypersusceptibility to influenza A, vesicular stomatitis virus, and encephalomyocarditis infections. This suggests that increasing the levels of AGO4 could be a potential treatment to contain viral infections. “The goal is to understand how our immune system works so we can create treatments that work against a range of viruses, rather than just vaccines against a particular one,” said Dr. Jeffrey.

Interestingly, AGO4 deficient cells showed increased viral titers in the IFN compromised cells. This demonstrated that AGO4 could achieve the ability to suppress viruses even without the IFN pathway (IFN-independent). The authors found higher levels of AGO-loaded virus-derived short interfering RNAs (vsiRNAs), the molecular marker of antiviral RNAi in macrophages infected with Influenza lacking the IFN and RNAi suppressor, NS1. These levels decreased in AGO4 deficient cells, demonstrating the antiviral RNAi activity of the protein.

In summary, the study has discovered the unique and powerful antiviral defense role performed by AGO4 in mammals. The next steps are to “determine how broad spectrum this is to any virus type,” said Dr. Jeffrey. “Then we need to discover how to boost AGO4 to ramp up protection against viral infections”. The study was published in Cell Reports.

Related reading: RNA Therapeutics: An Overview

References

1. https://www.cell.com/cell-reports/pdfExtended/S2211-1247(20)30030-9
2. https://www.massgeneral.org/news/press-release/Mass-general-hospital-researchers-identify-new-universal-target-for-antiviral-treatment
3. https://www.nature.com/articles/nmicrobiol2016250

Author

Rajaneesh K. Gopinath