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 report.

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 at UT Southwestern, a Howard Hughes Medical Institute Investigator, and senior author of the study. The study's lead author is graduate student Mingjian Du.

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 an inborn or innate, immune system that guards the body against threats it first encounters. The second is the adaptive immune system that deploys specialized immune cells to eradicate pathogens.

Innate immunity sensor

The innate immunity sensor cGAS sounds the alarm when it encounters DNA, either from pathogens or the body's cells in the case of the 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 secondary messenger that triggers innate immune responses. "The droplets act as microreactors to speed up reactions that churn out the small molecule cGAMP, which activates the immune system," Dr. Chen said.

"With a detailed understanding of the pathway, it will be possible to develop and design a variety of drugs for cancer and other diseases," said Dr. Chen, Director of the Center for Inflammation Research and a member in the Center for the Genetics of Host Defense who holds the George L. MacGregor Distinguished Chair in Biomedical Science.

"Several companies are working on potential treatments now. 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," said Dr. Chen. 

"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," said Dr. Chen.

This mechanism ensures that the immune system can fight infections without causing autoimmune reactions in healthy individuals. However, in some individuals who have elevated levels of self-DNA that come into contact with cGAS in their cells, autoimmune diseases can occur, Dr. Chen added.

"We previously studied a mouse model of autoimmune disease. In an experiment in which we could remove 50% of the cGAS enzyme, we found that doing so completely cured the disease in mice. Previously, that finding was difficult to explain. Now, this new model of a threshold effect for cGAS-DNA phase separation explains the finding," Dr. Chen said.