Old soldiers never die, they just fade away—which means that sometimes, they might come back. One old soldier, a veteran of antiviral battles that may go back billions of years, is an RNA-targeting system that can still be found in humans, albeit in remnants. The system, still performing RNA interference duties in plants and invertebrates, though pretty much retired humans, may still have value in our never-ending struggle against disease.
Evidence of the ancient system, which incorporates a protein called Drosha and enzymes called RNase III nucleases, was uncovered by scientists based at the Icahn School of Medicine at Mount Sinai. Led by Benjamin R. tenOever, Ph.D., these scientists traced the evolution of three generations of the ancient system. The scientists even speculate that the system goes back to the first prokaryotes. Whether the line back to single-celled organisms such as bacteria and archaea is continuous or not, variants of the RNA-based antiviral system, the scientists confirmed, may be found in all three domains of life.
Looking forward, the scientists suggest that the ancient system, which originally served to defend cells against viruses, could be recruited into new therapeutic campaigns, which would mobilize self-replicating RNAs to diseased tissue. By exploiting the ancient system, engineered forms of RNA could retain the desired properties of a virus, yet avoid engaging our more modern and, in this case, unwelcomed immune response.
The scientists detailed their work in a paper (“RNase III Nucleases from Diverse Kingdoms Serve as Antiviral Effectors”) that appeared June 28 in Nature. This paper describes how Drosha and related RNase III ribonucleases can elicit a unique RNA-targeting antiviral activity.
“Systemic evolution of ligands by exponential enrichment of this class of proteins illustrates the recognition of unbranched RNA stem loops,” wrote the article’s authors. “Biochemical analyses reveal that, in this context, Drosha functions as an antiviral clamp, conferring steric hindrance on the RNA-dependent RNA polymerases of diverse positive-stranded RNA viruses.”
The article’s authors also trace the evolution of three generations of the ancient antiviral defense system. They say that it first arose in cells that were infected by only one type of virus that was made of DNA. In these cells, some of the basic building blocks for life involved trimming special RNAs for a myriad of essential cellular processes. That tool was essentially a family of protein scissors called RNase III nucleases. They were used for many cellular functions but were adapted as an antiviral defense machine when eukaryotes—cells of a more modern type, with nuclei and mitochondria—and RNA viruses came onto the scene.
The war between pathogens and humans, among other life forms, then intensified and antiviral defenses evolved rapidly, quickly rendering this simple RNase III-based system ineffective. In its place, multiple other defense systems have developed, ultimately resulting in something called the interferon system now in use.
“The interferon system, unlike the RNase III defense, is a protein-based effort, instead of RNA-based, and it makes hundreds of thousands of different components that all try to fight a virus in different ways, but there is still a direct evolutionary connection between these systems,” noted Dr. tenOever. “All the major players in these pathways are related to each other, and a little bit of the early RNase III version still exists in our cells. Life in general never invents new things but just repurposes the old.”
The platform he is studying now uses engineered viruses or simple self-replicating RNAs that are extremely susceptible to this RNase III nuclease defense system. The scientists believe they can control the susceptibility of RNA or artificial viruses to this defense so that they have enough time to deliver a desired payload, whether it involves gene editing or therapeutic delivery of a biologic treatment.