A DNA-sensing enzyme forms droplets that act as tiny bioreactors creating molecules to stimulate innate immunity - the body's first response to infection, researchers report. The work, reported in the journal 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 senior author of the study. In 2012, the 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.
The innate immunity sensor cGAS sounds the alarm when it encounters DNA - either from pathogens or from the body's own cells in the case of autoimmune disease - in areas of the cell where that genetic material should not be. The lab 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 current study finds that when cGAS encounters pathogenic DNA, it binds with the DNA to create droplet-size, microreactors 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 microreactors to speed up reactions that churn out the small molecule cGAMP, which activates the immune system," the senior author 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 the senior author. "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. 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."
In the study, the authors found a threshold effect in the cGAS system. In test-tube studies they found that although DNA and cGAS are both needed to kick off the formation of membraneless droplets, a tiny amount of either DNA or the enzyme fails to sound the alarm.
When the levels of both DNA and cGAS reach a threshold, the liquid droplets form and the pathway kicks into gear. This threshold response allows cGAS to tolerate low levels of self-DNA that may come into contact with the enzyme inside the cells but to trigger a rigorous response when the DNA reaches a threshold level, such as in the case of viral infections, the senior author said.
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, the senior author added.
"We previously studied a mouse model of autoimmune disease. In an experiment in which we could remove 50 percent 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," the senior author said.
https://www.utsouthwestern.edu/newsroom/articles/year-2018/microreactors.html
http://science.sciencemag.org/content/early/2018/07/03/science.aat1022
Latest News
Mutations in noncoding DNA…
By newseditor
Posted 24 Apr
More influence of environme…
By newseditor
Posted 24 Apr
The assembly of the human c…
By newseditor
Posted 24 Apr
Wiring of the human neocortex
By newseditor
Posted 24 Apr
Abusive drugs hijack natura…
By newseditor
Posted 23 Apr
Other Top Stories
Promoting Sensitivity to Anti-folate Therapy in Breast Cancer
Read more
Microscopic drug 'depots' boost efficacy against tumors in animal m…
Read more
Mechanism of tumor suppressor mediated cell death in developing brain
Read more
Blocking pentose phosphate pathway to treat cancer
Read more
A glycolytic enzyme plays a major role in cancer
Read more
Protocols
A programmable targeted pro…
By newseditor
Posted 23 Apr
MemPrep, a new technology f…
By newseditor
Posted 08 Apr
A tangible method to assess…
By newseditor
Posted 08 Apr
Stem cell-derived vessels-o…
By newseditor
Posted 06 Apr
Single-cell biclustering fo…
By newseditor
Posted 01 Apr
Publications
Massively parallel screen u…
By newseditor
Posted 24 Apr
Distinct genetic and enviro…
By newseditor
Posted 24 Apr
Hippocampus-to-amygdala pat…
By newseditor
Posted 24 Apr
Integrative spatial analysi…
By newseditor
Posted 24 Apr
Time-series reconstruction…
By newseditor
Posted 24 Apr
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar