Corporate Banner
Satellite Banner
Scientific Community
Become a Member | Sign in
Home>News>This Article

Scientists Find Mechanism that Triggers Immune Responses to DNA

Published: Monday, December 24, 2012
Last Updated: Monday, December 24, 2012
Bookmark and Share
HHMI scientists have discovered the molecular pathway outside a cell’s nucleus in the cytosol.

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.”

Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,800+ scientific posters on ePosters
  • More than 4,000+ scientific videos on LabTube
  • 35 community eNewsletters

Sign In

Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

A Crisper View of DNA-Snipping Enzyme
HHMI scientists have created a portrait of a DNA-snipping protein called Cas9, a powerful research tool used in many labs for genome editing.
Saturday, February 08, 2014
Spontaneous Mutations Play a Key Role in Congenital Heart Disease
New research shows that about 10 percent of these defects are caused by genetic mutations that are absent in the parents of affected children.
Monday, May 13, 2013
A New View of Transcription Initiation
Reading the human genome.
Monday, March 04, 2013
Search for Epigenetic Decoder in Brain Cells Leads Scientists to Rett Syndrome
New analysis suggests that MeCP2 recognizes 5hmC in the brain and facilitates activation of the genes.
Monday, December 31, 2012
Erin O’Shea Named Vice President and Chief Scientific Officer at HHMI
O’Shea to begin her new duties part-time in January 2013 and transition to full-time in July 2013.
Monday, December 03, 2012
Susan Desmond-Hellmann Elected as HHMI Trustee
Desmond-Hellmann becomes one of 11 Trustees of the Institute.
Thursday, November 08, 2012
Autism Gene Screen Highlights Protein Network for Howard Hughes Medical Institute Scientists
Over the past decade, scientists have added many gene mutations to the list of potential risk factors for autism spectrum disorders -- but researchers still lack a definitive explanation of autism’s cause.
Thursday, April 05, 2012
Scientists Trace Origin of Recent Cholera Epidemic in Haiti
The finding supports the notion that the cholera bacteria fueling the outbreak arrived on the island via recent visitors.
Friday, December 10, 2010
New Tool Illuminates Connections Between Stem Cells and Cancer
HHMI researchers have a new tool to understand how cancers grow - and with it a new opportunity to identify novel cancer drugs.
Monday, February 22, 2010
Crash-Test Reveals DNA Traffic Control
Researchers have discovered that when DNA-copying enzymes run head-on into oncoming traffic, they kick the obstacles out of their way.
Friday, January 29, 2010
Mutations in Different Cells Cooperate to Set the Stage for Cancer
HHMI researchers have shown that distinct cancer-causing mutations in neighboring cells can cooperate to produce tumors.
Friday, January 15, 2010
Scientists Identify new Genetic Culprit for Intellectual Disability
Researchers link the girls’ intellectual disability to a change in a single “letter” in the TRAPPC9 gene.
Friday, December 18, 2009
Scientists Identify New Genetic Culprit for Intellectual Disability
HHMI researchers identified a genetic mutation that plays a role in intellectual disability.
Monday, December 14, 2009
Sticklebacks Hone Defenses through Small DNA Deletions
A single genetic adjustment is enough to help a small fish make a big change, HHMI researchers find.
Friday, December 11, 2009
Researchers Identify Gene that Spurs Deadly Brain Cancer
HHMI researchers identify a new factor necessary for the development of many forms of medulloblastoma.
Friday, December 04, 2009
Scientific News
New Tech Vastly Improves CRISPR/Cas9 Accuracy
A new CRISPR/Cas9 technology developed by scientists at UMass Medical School is precise enough to surgically edit DNA at nearly any genomic location, while avoiding potentially harmful off-target changes typically seen in standard CRISPR gene editing techniques.
New Class of RNA Tumor Suppressors Identified
Two short, “housekeeping” RNA molecules block cancer growth by binding to an important cancer-associated protein called KRAS. More than a quarter of all human cancers are missing these RNAs.
Biologists Induce Flatworms to Grow Heads and Brains of Other Species
Findings shed light on role of a new kind of epigenetic signaling in evolution, could yield clues for understanding birth defects and regeneration.
Turning up the Tap on Microbes Leads to Better Protein Patenting
Mining millions of proteins could become faster and easier with a new technique that may also transform the enzyme-catalyst industry, according to University of California, Davis, researchers.
Mathematical Model Forecasts the Path of Breast Cancer
Chances of survival depend on which organs breast cancer tumors colonize first.
Exploring the Causes of Cancer
Queen's research to understand the regulation of a cell surface protein involved in cancer.
Ancient Viral Molecules Essential for Human Development
Genetic material from ancient viral infections is critical to human development, according to researchers at the Stanford University School of Medicine.
Tardigrade's Are DNA Master Thieves
Tardigrades, nearly microscopic animals that can survive the harshest of environments, including outer space, hold the record for the animal that has the most foreign DNA.
The Secret Behind the Power of Bacterial Sex
Migration between different communities of bacteria is the key to the type of gene transfer that can lead to the spread of traits such as antibiotic resistance, according to researchers at Oxford University.
Farming’s in Their DNA
Ancient genomes reveal natural selection in action.
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,800+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,000+ scientific videos