Scientists find mechanism that triggers immune responses to DNA
(Medical Xpress)—Free-floating pieces of DNA in a cell's watery interior can mean bad things: invading viruses, bacteria, or parasites, ruptured cellular membranes, or disease. Genetic material is meant to be contained in a cell's nucleus or key organelles, and when it's loose, it's a sign for the immune system that something is wrong. Now, Howard Hughes Medical Institute scientists have discovered the molecular pathway responsible for detecting loose bits of DNA outside a cell's nucleus in the cytosol and setting off the resulting immune reaction.
The findings, published December 20, 2012, in two papers in the journal Science, could lead to treatments for autoimmune diseases such as lupus, in which ongoing immune reactions are often set off by loose pieces of DNA.
The cytosol of a cell is often passed over, its importance seemingly dwarfed by other parts of a cell. But in fact, says HHMI investigator Zhijian "James" Chen of the University of Texas Southwestern Medical Center, every molecule in the cytosol is carefully controlled and invaders are not welcome.
"The cytosol has to be very clean," says Chen. "If DNA gets in, that is actually very dangerous to cells."
Doctors have known since the early 20th century (even before they knew DNA's role of in carrying genetic information) that nucleic acids—DNA or RNA—could boost the activity of a person's immune system. And in recent years, Chen and other scientists have discovered some of the immune molecules key to this response. However, the known molecules are not responsible for detecting DNA, and Chen wanted to find out the molecules that are.
So his group, which includes lead authors of the Science papers Lijun Sun, a HHMI research specialist, and Jiaxi Wu, a graduate student at UT Southwestern, developed a biochemical assay to isolate the unknown molecules that sensed loose DNA. They isolated cytosol from cells that had been invaded by free bits of DNA and divided the liquid into different fractions. Each fraction of the total mix was added individually into other, fresh cells to test whether an immune reaction was set off, which would suggest that portion of the original cytosol contained the DNA sensor. Once they narrowed down the cytosolic fractions, Chen and his colleagues used mass spectrometry, a method of analyzing the chemical characteristics of a compound, as well as classical biochemistry to learn more about the molecules. They eventually narrowed their focus to two key players and worked out their roles.
One was a small molecule called cyclic GMP-AMP (cGAMP), which binds to and turns on one of the molecules already known to carry out the immune reaction against DNA, STING. cGAMP belongs to a class of compounds called cyclic di-nucleotides, which were known to function as signaling molecules in bacteria. Until now, however, they were not known to exist in multicellular organisms.
The other player was the enzyme that produces cGAMP, dubbed cGAMP synthase (cGAS). Chen's team found that cGAS bound directly to DNA in the cytosol, and the binding turned on its activity as an enzyme to catalyze the cGAMP synthesis.
"The cGAS enzyme recognizes all double-stranded DNA without any apparent sequence specificity," says Chen. "Which makes sense because an organism wants to recognize all sorts of DNA from different sources. As long as DNA gets into the wrong place, which is the cytosol, cGAS is there to detect it and sets off the immune reaction."
The discovery by Chen's group outlines the entire response of the cell from detecting free DNA in the cytosol to activating the STING-mediated immune response. But there are still details that need to be worked out.
"One of the things we need to do next is solve the structure of cGAS and try to understand how DNA binding activates the enzyme," says Chen. And understanding the structure can help with his next goal: designing compounds that can block the enzyme. In autoimmune diseases including lupus and Sjögren's syndrome, the immune system is put into overdrive attacking a person's own cells. One factor that sets off this immune response is loose DNA in these cells, so it's likely that cGAMP and cGAS play a role. By blocking a cell's response to its own DNA, the constant immune response in affected individuals could be dampened.
"We hope we can go on to identify chemical inhibitors of this enzyme," says Chen. "Such inhibitors could be developed into therapies for autoimmune diseases."
Journal reference: Science
Provided by Howard Hughes Medical Institute
- Researchers reveal crucial immune fighter role of the STING protein Jun 18, 2012 | not rated yet | 0
- How unchecked alarms can spark autoimmune disease Nov 29, 2011 | not rated yet | 0
- Researchers identify key molecular step to fighting off viruses Apr 21, 2010 | not rated yet | 0
- Accumulated bits of a cell's own DNA can trigger autoimmune disease Aug 21, 2008 | not rated yet | 0
- New type of bacterial protection found within cells Nov 13, 2012 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
Ratio of Hydrogen of Oxygen in Dessicated Animal Protein
May 13, 2013 As an experiment, for the past few months I've been consuming at least one portion of Jell-O or unflavored Knox gelatin per day. I'm 64, in very...
Alcohol and acetaminophen
May 13, 2013 Edit: sorry for the typo in the title , can't edit I looked around on google quite a bit and it's very hard to find precise information on the...
Marie Curie's leukemia
May 13, 2013 Does anyone know what might be the cause of Marie Curie's cancer
- More from Physics Forums - Medical Sciences
More news stories
Nearly 20 percent of kidneys that are recovered from deceased donors in the U.S. are refused for transplant due to factors ranging from scarring in small blood vessels of the kidney's filtering units to the organ going too ...
Medical research 9 hours ago | 5 / 5 (1) | 0 |
Discovery of circadian clock in mice hair reveals period of time when damage from radiotherapy can be quickly repaired
Discovering that mouse hair has a circadian clock - a 24-hour cycle of growth followed by restorative repair - researchers suspect that hair loss in humans from toxic cancer radiotherapy and chemotherapy ...
Medical research 9 hours ago | 5 / 5 (2) | 1 |
Salamanders' immune systems are key to their remarkable ability to regrow limbs, and could also underpin their ability to regenerate spinal cords, brain tissue and even parts of their hearts, scientists have ...
Medical research 10 hours ago | 4.8 / 5 (5) | 2 |
New research from the University of Southampton has shown that blind and visually impaired people have the potential to use echolocation, similar to that used by bats and dolphins, to determine the location of an object.
Medical research 13 hours ago | not rated yet | 1 |
A novel vaccine study from South Dakota State University (SDSU) will headline the groundbreaking research that will be unveiled at the American Association of Pharmaceutical Scientists' (AAPS) National Biotechnology Conference ...
Medical research 13 hours ago | not rated yet | 0
Early-life exposure to traffic-related air pollution was significantly associated with higher hyperactivity scores at age 7, according to new research from the University of Cincinnati (UC) and Cincinnati Children's Hospital ...
1 hour ago | not rated yet | 0 |
Bacteria resistant to the antibiotic colistin are also commonly resistant to antimicrobial substances made by the human body, according to a study in mBio, the online open-access journal of the American Society for Microb ...
1 hour ago | not rated yet | 0
(Medical Xpress)—A research team, led by Jeremy Barr, a biology post-doctoral fellow, unveils a new immune system that protects humans and animals from infection.
7 hours ago | 4.5 / 5 (11) | 2 |
New research suggests that a compound abundant in the Mediterranean diet takes away cancer cells' "superpower" to escape death. By altering a very specific step in gene regulation, this compound essentially re-educates cancer ...
10 hours ago | 4.8 / 5 (10) | 2 |
Researchers have pinpointed a catalytic trigger for the onset of Alzheimer's disease – when the fundamental structure of a protein molecule changes to cause a chain reaction that leads to the death of neurons ...
10 hours ago | 5 / 5 (3) | 0 |
Turns out, that old "practice makes perfect" adage may be overblown. New research led by Michigan State University's Zach Hambrick finds that a copious amount of practice is not enough to explain why people ...
8 hours ago | 3.3 / 5 (10) | 0 |