DDX39B seen as ‘guardian’ in autoimmune attacks that drive MS

The protein DDX39B is a master regulator of immune tolerance, or the immune system’s ability to distinguish self from potentially harmful nonself molecules, and helps to control the development of immune cells that are key for this process, a new study shows.

Findings suggest that activating DDX39B with small molecules might be a viable strategy for treating autoimmune diseases like multiple sclerosis (MS), where the immune tolerance process is disrupted.

The study, “The RNA helicase DDX39B activates FOXP3 RNA splicing to control T regulatory cell fate,” was published in eLife.

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DDX39B changes the expression of genes considered to be MS risk factors

MS is caused by inflammation that damages the brain and spinal cord. It’s not known exactly what triggers this inflammation to start, but genetics are known to play a role in influencing disease risk.

The DDX39B protein (also known as UAP56) acts as a regulator of gene expression — in essence, it helps to turn other genes off or on. Prior studies have shown that DDX39B is important for regulating the expression of a gene called IL7R, which has been linked to MS risk.

This suggests that DDX39B may itself affect the risk of MS or other autoimmune diseases.

To find out, a team led by scientists in the U.S. conducted a series of experiments in cell models, measuring how the expression of hundreds of MS-related genes changed when cells were engineered to lack the DDX39B protein.

Results showed that removing DDX39B significantly changed the expression, or activity, of several — 41 out of 558 — of these MS-related genes. More specifically, removing DDX39B led to increased expression of genes that are associated with a higher MS risk, and with a lower expression of genes associated with a reduced MS risk.

“These data strongly suggested a shift of gene expression signature from MS-protective to MS-pathogenic upon DDX39B depletion, and provide support for a protective role for DDX39B in MS risk,” the researchers wrote.

Closer inspection revealed that one of the DDX39B-regulated genes was FOXP3. This gene plays a critical role in the development and activation of regulatory T-cells (Tregs).

Tregs are a type of immune cell that is crucial for maintaining immune tolerance — the immune system’s ability to recognize the body’s own healthy tissues and establish they are not targets to attack. Autoimmune diseases like MS are fundamentally driven by a breakdown of normal immune tolerance as, by definition, they are driven by the immune system accidentally attacking healthy tissue. Strategies to activate T-cells are being investigated as potential MS treatments.

‘Important guardian of immune tolerance’ may aid ‘truly’ targeted treatments

Further experiments demonstrated that the DDX39B protein regulates the FOXP3 gene by helping to edit its messenger RNA, an intermediary molecule made when the gene is read to produce protein. The scientists identified, at the molecular level, how the DDX39B protein interacts with FOXP3 RNA.

Taking these data collectively, results show that DDX39B is needed for the normal activity of the FOXP3 gene. “Given the importance of FOXP3 in autoimmunity, this work cements DDX39B as an important guardian of immune tolerance,” the researchers wrote.

“It is remarkable that a protein that unwinds RNA is a central player in how we recognize our cells as our own, not to be confused with invading pathogens,” Mariano Garcia-Blanco, MD, PhD, a study co-author at the University of Virginia, said in a university press release.

These findings imply that activating DDX39B might be a viable way of treating autoimmune diseases like MS, the researchers noted.

“In cases of autoimmune diseases, we would want to activate DDX39B with small-molecule agonists [activators], for which there is strong pre-clinical precedent,” said Chloe Nagasawa, a graduate student in Garcia-Blanco’s lab and study co-author.

“We believe that basic understanding of molecular mechanisms underpinning immune tolerance will open paths to truly targeted therapy,” Nagasawa added.