A mechanism for Z-DNA mediated cell death and inflammation

A mechanism for Z-DNA mediated cell death and inflammation

Researchers describe in the journal "Nature" their discovery of a new mechanism that could contribute to the pathogenesis of inflammatory diseases. The scientists found that ZBP1, a protein known to ward off invading viruses, is activated by an unusual form of cellular genetic material (Z-nucleic acids), which can lead to cell death and inflammation.

Z nucleic acids are double-stranded DNA and RNA molecules with an unusual left-handed double helix structure, unlike the classic right-handed Watson-Crick double helix. Z nucleic acids were discovered over 40 years ago, but their biological function has so far been poorly understood. The research group studied the role of Z-DNA Binding Protein (ZBP1), one of only two proteins in mammals that can recognize Z nucleic acids. 
Surprisingly, the researchers found evidence in previous studies that ZBP1 can cause cell death and inflammation even without a virus infection. They found that when RIPK1 - a protein that suppresses ZBP1 - malfunctioned, ZBP1 was activated and triggered an inflammatory type of cell death called necroptosis. A key question in the current study was how ZBP1 can be triggered without a virus infection.

Through experiments on the mouse model organism, the scientists found that the inflammatory activity of ZBP1 is based on its ability to bind Z-nucleic acids, which suggests that it is activated by Z-shaped nucleic acids that existed in the cell. 

Another question was what type of endogenous nucleic acids is bound by ZBP1. "We were able to show that ZBP1 binds to double-stranded RNA," said the senior author. “We currently lack the experimental methodology to show that it has a Z-structure. But based on all available structural studies, we interpret our results so that ZBP1 with its Zá domains binds to endogenous Z-RNA. ”

Double-stranded RNA (dsRNA) is rare in cells, but is generated during the replication of certain viral genomes and is a ligand that activates ZBP1 during virus infection. The scientists suspected that the cellular dsRNA is derived from endogenous retro elements, which are forms of parasitic DNA that either come from old retrovirus infections or from active retrotransposons, also known as "jumping genes", which make up more than half of the human and mouse genomes turn off. 

To clarify the possible role of endogenous retro elements as a source of dsRNA, the team did computer analysis of mouse skin RNA sequencing data and showed that most of the complementary, probably double-stranded, RNA came from single groups of endogenous retro elements. These findings suggested that recognition of cellular dsRNA, most likely derived from endogenous retroelements, activates ZBP1 and leads to cell death and inflammation. This mechanism could be relevant to the pathogenesis of inflammation in humans, especially in patients with mutations in proteins that suppress ZBP1, such as RIPK1. 

"Z-shaped nucleic acids have been mysterious to us for many years," says the senior author. “At the moment, our only means of exploring their function is to study the proteins that recognize them. We have made some progress, but the challenge is to understand why, where and how they form in a cell and why. ”

A particularly fascinating aspect is the connection with endogenous retro elements. “We currently understand very little about how these genome parasites affect our health. It appears that in the course of evolution, some retrotransposons that can mimic a viral infection have been recruited as useful partners in our cells' response to damage, stress, or real infection. However, this partnership can also go wrong and cause illness, ”explains the author. 

“Just like during a viral infection, ZBP1 recognition of Z-RNA produced by endogenous retro elements could be a powerful trigger for cell death and inflammation and cause disease. We are still at the very beginning and have a long way to go, but understanding the underlying mechanisms could one day lead to novel therapies for human diseases, ”concludes the senior author.