In a new study, researchers from Weill Cornell Medical College in the United States found that messenger RNA (mRNA) contains chemical markers critical for antiviral defense against cells. This finding uncovers 50 years of mystery about the purpose of these chemical modifications and suggests that misdirected mRNA modifications may underlie some autoimmune and inflammatory diseases. The results were published online in Nature journal on 1 February 2023 with the title "mRNA ageing shapes the Cap2 methylome in mammalian mRNA".
Specifically, they found that the presence of a common chemical modification at a specific site on an mRNA molecule- -methylation- - -provides additional protection to the mRNA, protecting it from the disruption of antiviral immune mechanisms.
Dr. Samie Jaffrey, the corresponding author of the paper and the professor of Pharmacology at Weill Cornell Medical College, said, " We have known since the 1970s that methyl modifications to some extent underlie the normal functioning of mRNA. It is very gratifying, therefore, to finally have such a knowledge of its exact role.”
The mRNA is copied by active genes, which transmit the instructions outward from the DNA in the nucleus to the main part of the cell, where they are translated into proteins.
The Jaffrey lab has studied the mechanisms used by cells to regulate mRNA, for example, to promote or inhibit their translation into proteins. One of these regulatory mechanisms is the addition of chemical modifications to the mRNA. These chemical modifications often involve methyl modifications. In previous research work, the Jaffrey team developed methods to detect one of these methyl modifications, methyl-adenosine (m6A) - -, which controls mRNA stability in cells. Change in m6A can lead to different types of cancer.
However, mRNA often contains another chemical modification called Cap 2. In the new study, Jaffrey and Vladimir Despic, the first author of the paper and postdoctoral research assistant at the Jaffrey lab, studied the chemical modification, whose function was remained a mystery.
The mRNA, just like the DNA that generates them by transcription, is all composed of a string of bases called nucleotides. When an mRNA is made, its first nucleotide is "covered (also known as capping)" by a small organic molecule. The first nucleotide is also modified by attaching a group called the methyl group.
When this type of methylation is present on the first nucleotide, the mRNA is known to have the standard "Cap 1" cap, which is known to help protect the mRNA from the immune mechanisms that monitor anything resembling a viral RNA at the cell membrane.
Intrigingly, some mRNA gain additional methylation at their second nucleotide. The question of why this additional "Cap 2" methylation occurs, and why it appears on some mRNA instead than others, is almost impossible to answer – mainly because biologists do not have a good way to detect which mRNA have Cap 2 instead of Cap 1.
Jaffrey and Despic started their research by developing one such method- -what they call CLAM-Cap-seq- - - - -. With this approach, they found that Cap 2 methylation can occur on any mRNA but at a relatively slow rate, so it tends to be found only on those mRNA that have been present in the cytoplasm for a long time.
Ultimately, they found evidence that while Cap 1 greatly reduces the ability of the mRNA to trigger cellular antiviral mechanisms, Cap 2 provides crucial additional protection. They observed that when cellular mRNA is only Cap 1 type, these cellular mRNA activate inflammatory antiviral mechanisms in cells, even in the absence of virus.
But, these authors found that too much Cap 2 is also bad. When their designed cells rapidly incorporated Cap 2 into the mRNA, they found that the mRNA of invading viruses began to acquire Cap 2, protecting them from immune attack and allowing these viruses to grow uncontrolled. Jaffrey Said, " We think that Cap 2 methylation occurs very slowly, not very quickly, to reduce the chance that it eventually hides the rapidly replicated viral RNA from being discovered by the immune system.”
These findings, in addition to solving the long-standing Cap 2 puzzle, open up new directions for translational research.One possibility Dr Jaffrey now pursues is that dysfunction of the Cap 1 / Cap 2 process underlies some common inflammatory and autoimmune diseases such as lupus and rheumatoid arthritis, and that correction for this dysfunction could be a new treatment for these diseases.
Another possibility, he says, is to boost antiviral immunity by inhibiting Cap 2 in the absence of viral infections without a better treatment.
Jaffrey Said, " We are also studying the possibility of using Cap 2 modification by reducing the inflammatory effects of mRNA-based therapeutic drugs (including vaccines) in cells.
