Nav: Home

Innate immunity

September 13, 2017

In higher organisms, the genetic material is normally confined to the cell nucleus and the membrane-bounded organelles known as mitochondria. Any DNA found in the cytoplasm that surrounds these compartments must therefore originate either from damage to the nucleus or mitochondria, or from invasive bacterial pathogens or DNA viruses. The enzyme cGAS acts as a sensor of such misplaced DNA and "informs" the cell's innate immune system of the presence of an infection. Now a team led by Prof. Karl-Peter Hopfner, in collaboration with his colleague Prof. Veit Hornung at the LMU Gene Center and Prof. Heinrich Leonhardt of the LMU Biomedical Center, has discovered why the length of the cytoplasmic DNA has an impact on the efficiency with which it is detected. The researchers found that the DNA and the enzyme interact to form a ladder-like complex, and went on to demonstrate that this structure must exceed a certain length in order to activate the innate immune system. The new findings appear in the leading journal Nature.

cGAS binds to cytosolic DNA as a homodimer (i.e., the functional form of the enzyme consists of two identical subunits). Binding triggers an enzymatic reaction that results in the formation of a cyclic messenger molecule that induces the synthesis of immunostimulatory proteins called interferons. Earlier studies had shown that, in cells containing equal amounts of cytosolic DNA, longer DNA strands activate this reaction much more efficiently than do short strands.

"To determine how cGAS 'measures' the length of the DNA, we crystallized a complex consisting of cGAS dimers and longer DNA fragments and determined its structure by X-ray diffraction," Hopfner explains. It turns out that the complex is structured like a ladder with double-stranded DNA(s) forming the uprights between which the dimers are slotted in to form 'rungs'. The uprights may be formed either by two separate DNAs or by a single U-shaped DNA molecule. Formation of the ladder structure is required to sufficiently stabilize the active enzyme dimers to allow them to synthesize the signal molecule cGAMP: "The more rungs are inserted, the more stable the complex becomes, as neighboring dimers stabilize one another," says Liudmila Andreeva, lead author of the paper. "We were able to construct a mathematical model that accounts for this mechanism."

If the DNA is so short that only a single rung can form, the complex is unstable and rapidly dissociates. "The complex functions like a zipper. If only one of the projections interlocks it can be easily displaced, but when many are slotted into place, the central part cannot fall apart," as Hopfner explains. Certain other proteins can facilitate initiation of the ladder structure by causing the DNA to form U-turns that allow the first cGAS dimers to be inserted, which are readily followed by others. The LMU team was able to show that certain stress related and DNA packaging proteins in the nucleus, in bacteria and mitochondria stimulate cGAS activation by structuring DNA.

The researchers believe that the requirement for DNA of a minimal length, and the formation of U-turns, helps the innate immune system to avoid reacting needlessly to false alarms: Short cytosolic DNA molecules may be derived from processes within the cell itself. In order to target DNA from pathogens, it obviously helps if the sensor reacts more effectively to larger DNA fragments.



cGAS senses long and HMGB/TFAM bound U-turn DNA by forming protein-DNA ladders

Liudmila Andreeva, Björn Hiller, Dirk Kostrewa, Charlotte Lässig, Carina C. de Oliveira Mann, David J. Drexler, Andreas Maiser, Moritz Gaidt, Heinrich Leonhardt, Veit Hornung, Karl-Peter Hopfner

Nature 2017

DOI: 10.1038/nature23890

Ludwig-Maximilians-Universität München

Related Dna Articles:

Penn State DNA ladders: Inexpensive molecular rulers for DNA research
New license-free tools will allow researchers to estimate the size of DNA fragments for a fraction of the cost of currently available methods.
It is easier for a DNA knot...
How can long DNA filaments, which have convoluted and highly knotted structure, manage to pass through the tiny pores of biological systems?
How do metals interact with DNA?
Since a couple of decades, metal-containing drugs have been successfully used to fight against certain types of cancer.
Electrons use DNA like a wire for signaling DNA replication
A Caltech-led study has shown that the electrical wire-like behavior of DNA is involved in the molecule's replication.
Switched-on DNA
DNA, the stuff of life, may very well also pack quite the jolt for engineers trying to advance the development of tiny, low-cost electronic devices.
Researchers are first to see DNA 'blink'
Northwestern University biomedical engineers have developed imaging technology that is the first to see DNA 'blink,' or fluoresce.
Finding our way around DNA
A Salk team developed a tool that maps functional areas of the genome to better understand disease.
A 'strand' of DNA as never before
In a carefully designed polymer, researchers at the Institute of Physical Chemistry of the Polish Academy of Sciences have imprinted a sequence of a single strand of DNA.
Doubling down on DNA
The African clawed frog X. laevis genome contains two full sets of chromosomes from two extinct ancestors.
'Poring over' DNA
Church's team at Harvard's Wyss Institute for Biologically Inspired Engineering and the Harvard Medical School developed a new electronic DNA sequencing platform based on biologically engineered nanopores that could help overcome present limitations.

Best Science Podcasts 2017

We have hand picked the best science podcasts for 2017. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: Radiolab

Oliver Sipple
One morning, Oliver Sipple went out for a walk. A couple hours later, to his own surprise, he saved the life of the President of the United States. But in the days that followed, Sipple's split-second act of heroism turned into a rationale for making his personal life into political opportunity. What happens next makes us wonder what a moment, or a movement, or a whole society can demand of one person. And how much is too much?  Through newly unearthed archival tape, we hear Sipple himself grapple with some of the most vexing topics of his day and ours - privacy, identity, the freedom of the press - not to mention the bonds of family and friendship.  Reported by Latif Nasser and Tracie Hunte. Produced by Matt Kielty, Annie McEwen, Latif Nasser and Tracie Hunte. Special thanks to Jerry Pritikin, Michael Yamashita, Stan Smith, Duffy Jennings; Ann Dolan, Megan Filly and Ginale Harris at the Superior Court of San Francisco; Leah Gracik, Karyn Hunt, Jesse Hamlin, The San Francisco Bay Area Television Archive, Mike Amico, Jennifer Vanasco and Joey Plaster. Support Radiolab today at
Now Playing: TED Radio Hour

Future Consequences
From data collection to gene editing to AI, what we once considered science fiction is now becoming reality. This hour, TED speakers explore the future consequences of our present actions. Guests include designer Anab Jain, futurist Juan Enriquez, biologist Paul Knoepfler, and neuroscientist and philosopher Sam Harris.