Two new studies published in Nature recently reveal the structure and mechanism of an enzyme called cGAS that detects DNA found in the wrong place inside mammal cells and triggers an immune response. The researchers believe their findings open avenues for developing new cancer and autoimmune disease treatments.
Mammal cells keep their DNA tightly packed inside their nuclei or their mitochondria power plants. So when DNA is founAd in the cell fluid outside of these enclosures or organelles, the immune system reacts as if it has come from a pathogen like a virus or bacteria and sets about releasing interferons, proteins that signal killer cells and macrophages to eliminate the unwanted material.
However, sometimes the DNA isn't from a pathogen, but from the cell itself, perhaps it escaped its tightly packed organelle as a result of some cell trauma or shock. In this case, the immune reaction could be highly inappropriate, and so you have the beginnings of an autoimmune disease.
A little while ago, scientists identified cGAS as the protein that senses DNA that is "out of place" in the cell fluid or cytosol.
Now Karl-Peter Hopfner, a professor in the Department of Biochemistry and Gene Center at Ludwig-Maximilians-University (LMU) in Munich, and colleagues, have determined the three-dimensional structure and mechanism of this DNA detector.
In one of the Nature studies, the researchers describe not only the detailed structure of the cGAS molecule, but also the complex formed when it binds to DNA.
With the collaboration of Veit Hornung, a professor in the Institute for Clinical Chemistry and Clinical Pharmacology at the University of Bonn, the team worked out how cGAS identifies and is activated by cytosolic DNA.
When the DNA binds to cGAS, it changes the structure of the enzyme in a way that makes it trigger the production of another molecule called cyclic dinucleotide. This in turn activates a protein that can travel through cell membranes and start the release of interferons.
In a statement, Hornung explains how in the second Nature study, they "also determined the structure of the dinucleotide, and show that it represents a previously unknown form of this class of signaling molecule".
The team was surprised and excited when it found the structure and mechanism of cGAS is similar to that of another enzyme that triggers an immune response when it detects genetic material or RNA from a virus in the cell's cytosol.
Hopfner says:
"With this finding we have the first evidence for a mechanistic and evolutionary link between DNA- and RNA-induced immune reactions."
From this deeper understanding of how the immune system triggers interferons, the findings could open two new avenues for treatments.
One avenue could be to improve cancer treatments by stimulating interferons to target tumors, and the other could be new autoimmune disease treatments that stop interferons from attacking healthy cells.
In another study published recently in Cell Host & Microbe, researchers at Keck School of Medicine of the University of Southern California describe how they discovered the interferon-stimulated antiviral protein IFITM3 disrupts cholesterol balance between cells to block viral entry.
Article Reference： "Structural mechanism of cytosolic DNA sensing by cGAS"; Filiz Civril, Tobias Deimling, Carina C. de Oliveira Mann, Andrea Ablasser, Manuela Moldt, Gregor Witte, Veit Hornung, and Karl-Peter Hopfner; NaturePublished online 30 May 2013; DOI:10.1038/nature12305; Link to Abstract.
"cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING"; Andrea Ablasser, Marion Goldeck, Taner Cavlar, Tobias Deimling, Gregor Witte, Ingo Röhl, Karl-Peter Hopfner, Janos Ludwig, and Veit Hornung; NaturePublished online 30 May 2013; DOI:10.1038/nature12306; Link to Abstract.
Additional source: Ludwig-Maximilians-University.