Enzyme That Finds Unwanted DNA In Cells Revealed

Date: Jun-05-2013Two 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 found 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.

Written by Catharine Paddock PhD

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