Researchers at the NYU School of Medicine have discovered a genetic regulatory mechanism that may influence the ability of the immune system to protect against viral infection. The mechanism may also play an important role in autoimmune disease.
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The team found that chemical changes at certain sites on messenger RNA (mRNA) regulate the production of interferon beta, a protein involved in inflammation and the activation of immune cells that kill viral particles.
As reported in the journal Genes and Development, the study revealed how two enzymes influence production of IFN-beta by determining whether a methyl group is attached to a certain position on adenosine, a nucleotide in the mRNA code.
Methylation of adenosine at the nitrogen-6 (N-6) position by an enzyme called m6A methyltransferase creates a mark that is counter-acted by another enzyme called ALKBH5 that removes the mark.
Our study found that the cellular machinery that controls adenosine methylation on position N-6 plays a fundamental role shaping the immune response of human cells.”
Ian Mohr, Senior Author
The researchers discovered that, together with other proteins, this pair of enzymes control how much interferon beta mRNA is produced in response to human cytomegalovirus (HMCV) infection, which begins by injecting its DNA into host human cells.
They found that inhibiting the enzyme that installs the methylation mark at N-6, increased interferon production, while inhibiting the enzyme that removes the mark, reduced its production.
The author’s also discovered that the proteins involved in editing RNA methylation control the production of interferon beta within uninfected cells, once human DNA had been lost from the nucleus or mitochondria.
This can happen when DNA becomes damaged by radiation or chemicals or when age-related changes occur in the nucleus or mitochondria.
Since misplaced DNA is known to induce inflammation in autoimmune and inflammatory disease, as well as during the aging process, the findings may represent a potential new approach to treatments.
Many diseases, such as lupus, are associated with excess interferon production related to the sensing of misplaced DNA, and our new findings suggest that interfering with enzymes that chemically modify mRNA may represent new ways to treat these conditions.”
Ian Mohr, Senior Author