Team Shows How Dicer Protein Detects and Destroys Viral Invaders

When viruses infect the body’s cells, those cells face a difficult problem. How can they destroy viruses without harming themselves?  Researchers at University of Utah Health have discovered a protein that cuts apart the genetic material of harmful invading viruses. Their research shows how the protein detects the intruders and processes them for destruction to protect cells and prevent the spread of infection.

“Fighting viruses is essential for survival,” says Brenda Bass, Ph.D., distinguished professor of biochemistry at University of Utah Health, who co-led the study with assistant professor Peter Shen, Ph.D. “It is fascinating to see how biology has evolved to solve this problem.”

The research (“Dicer Uses Distinct Modules for Recognizing dsRNA Termini”) appears in Science.

Drs. Bass, Shen, and their colleagues have closely examined the protein, named Dicer, which was initially identified in the fruit fly Drosophila melanogaster. Now that they know how the fly protein works, they may be able to develop methods to overcome viruses that cause human disease, says Dr. Bass.

Viruses spread infection by replicating and copying their genomic material inside the cell, and during this process make double-stranded RNA (dsRNA). “Dicer rids the cell of the offending intruder by grabbing hold of the rope-like dsRNA, chopping it into pieces as it reels it in,” note the researchers.

One small difference existing between viral and cellular dsRNA is responsible for identifying the virus as an unwanted intruder – that is, the ends of both strands of viral dsRNA are even, while one strand of cellular dsRNA is a tad longer at the end.

“Dicer has to be careful about what it destroys because otherwise it would shut down the cell,” explains graduate student and first author Niladri Sinha. “Seeing how Dicer works answers a long-standing question of how antiviral receptors can discriminate between ‘self’ from ‘nonself’.”

This property is important for more than one reason. As a part of normal cell function, Dicer slices dsRNA made by the cell, too. For the first time, this study shows that this single machine processes dsRNA from viruses using a completely different mechanism.

When Dr. Bass first started investigating the protein, she noted it had a region known as the helicase domain, but no one knew why. She decided to collaborate with Dr. Shen to determine whether seeing the protein could help them answer that question.

They flash-froze and analyzed Dicer using cryo-electron microscopy (cryo-EM), but it was not easy to get a picture of the protein interacting with viral RNA. Dicer is small even by cryo-EM standards. It also bends and moves, making it difficult to pin down.

Using biochemistry, the scientists discovered that the mysterious helicase domain defines the previously unknown mechanism for destroying virus: It recognizes the intruder and reels it in just before the kill. Importantly, once the helicase grabs hold of the viral material, it doesn’t let go, improving its chances for eradicting infection.

“What I love about this is that we had no idea how the enzyme was working. Just by looking at it, we came upon something unexpected,” says Dr. Shen.

It’s possible that Dicer only functions this way in flies. But biology has a habit of reusing tools that work well, notes Dr. Shen. “I’m sure people will be thinking that perhaps under certain conditions, or in the presence of additional protein factors, human Dicer could act like the fly’s.”

Such a discovery could give scientists new ways to control viral infection, and our body’s response to infection.