A DNA-sensing enzyme forms droplets that act as tiny bioreactors creating molecules to stimulate innate immunity – the body’s first response to infection, UT Southwestern researchers found. The work, reported in Science, could lead to novel treatments for infections, autoimmune disease, and cancer.
A hallmark of all three of those illnesses is the presence of DNA – either foreign or self – in the cell’s gel-like interior known as the cytoplasm, said Dr. Zhijian “James” Chen, Professor of Molecular Biology, a Howard Hughes Medical Institute Investigator, and senior author of the study.
In 2012, Dr. Chen’s laboratory discovered the enzyme cyclic GMP-AMP synthase (cGAS), which acts as a sensor in a cellular alarm system for innate immunity. The body has two immune systems. The first is the innate immune system, the body’s first defense against threats. The second is the adaptive immune system that deploys specialized immune cells to eradicate pathogens.
The innate immunity sensor cGAS sounds the alarm when it encounters DNA – either from pathogens like viruses or bacteria or from the self in the case of autoimmune disease – in areas of the cell where that genetic material should not be. Dr. Chen also identified the small molecule cGAMP, which is produced by the enzyme cGAS and functions as a second messenger that triggers innate immune responses.
The current study finds that when cGAS encounters pathogenic DNA, it binds with the DNA to create droplet-size, micro reactors that hold together despite the lack of a membrane. The study identifies the mechanism that holds the droplets together as liquid phase separation, which is similar to the way oil separates from vinegar after a bottle of salad dressing is shaken.
“The droplets act as micro reactors to speed up reactions that churn out the small molecule cGAMP, which activates the immune system,” said Dr. Chen, also Director of the Center for Inflammation Research and a member of the Center for the Genetics of Host Defense. “With a detailed understanding of the pathway, it will be possible to develop and design a variety of drugs for cancer and other diseases.”
Several companies are working on potential treatments now, he said.
“For autoimmune diseases such as lupus – in which cGAS is aberrantly turned on by self-DNA in the cell’s interior – the goal is to find cGAS inhibitors. With infections, it would be good to enhance the body’s immune defense. There is also the hope of finding drugs that stimulate the cGAS pathway to boost the effects of cancer immunotherapy,” he said.
The study’s lead author is Ph.D. student Mingjian Du. The investigation received support from the Lupus Research Alliance, the Cancer Prevention and Research Institute of Texas (CPRIT), The Welch Foundation, and the HHMI.