UT Southwestern researchers are examining how an enzyme might someday be used to manipulate the body’s innate immunity – our first response to infection. It could work in different ways to fight different diseases. Ramping up the body’s immunity could help fight infections and potentially even boost the immune response against cancer cells. Dialing down immunity, on the other hand, could help treat a variety of autoimmune diseases, including lupus.
Researchers know that the DNA from viruses, bacteria, and parasites makes its way into the cytoplasm of our cells. They also know that certain infections, autoimmune diseases, and cancer all have a common thread – they show signs of DNA in the cells’ cytoplasm.
Back in 2012, UT Southwestern researchers discovered that an enzyme, called cyclic GMP-AMP synthase (cGAS), can bind to this DNA when it comes across it in the cytoplasm. When that happens, the enzyme produces a small molecule called cGAMP.
“This molecule triggers a powerful immune response,” explains Dr. Zhijian “James” Chen, Ph.D., Professor of Molecular Biology at UT Southwestern, a Howard Hughes Medical Institute Investigator, and senior author of the research. “It alerts the immune system to defend against infections from these pathogens.”
For his discovery of the cGAS enzyme, Dr. Chen was recently named winner of the prestigious 2019 Breakthrough Prize in Life Sciences.
New Study Expands on Research
Scientists wanted to figure out how this enzyme is regulated. They wanted to understand how the enzyme could trigger a strong response to foreign DNA from infections without causing a response against our own DNA.
That’s because if the enzyme comes into contact with our own DNA, it can trigger autoimmune diseases. “It’s a double-edged sword,” Dr. Chen says. “We need it to defend against infection, but if it’s improperly triggered by our own DNA it can cause these auto-immune and inflammatory diseases.”
The scientists designed a new study. In their research, they discovered something interesting – a tiny amount of either DNA or the enzyme fails to trigger a response. But when the enzyme and the DNA reach a certain concentration, the enzyme triggers the formation of special droplets.
“Within this concentrated droplet, the enzyme becomes activated,” Dr. Chen says. The droplet acts like a microreactor within the cell, accelerating the enzyme to trigger the immune response. “It speeds up the reactions that churn out the small molecule cGAMP, which activates the immune system.”
The study, published in Science in 2018, explains how there can be some DNA in the cells, but if it stays below a certain threshold, it doesn’t trigger activation of the enzyme or the creation of these droplets. When there’s enough DNA, as with a viral infection, the enzyme binds with it and these powerful droplets form.
A Pathway With Potential
“With a detailed understanding of this pathway, it will be possible to design and develop a variety of drugs for cancer and other diseases,” Dr. Chen says. Researchers could potentially identify and design molecules that will inhibit the enzyme and use them to treat a range of autoimmune diseases.
They could also potentially take the opposite approach to treat people with cancer – they would want to activate the enzyme, given that a lot of people with cancer don’t have adequate immunity. Also, they hope to someday use it to boost the immune response against tumor cells. “There is the hope of finding drugs that stimulate the cGAS pathway to boost the effects of cancer immunotherapy,” Dr. Chen says.
Dr. Chen is Director of the Center for Inflammation Research and a member of the Center for the Genetics of Host Defense. He holds the George L. MacGregor Distinguished Chair in Biomedical Science. The study’s lead author is graduate student Mingjian Du.
The Vanguard
Learn about the latest advances in cancer care, research, and technology inside this publication from UT Southwestern’s Simmons Cancer Center.
