Nature: Significant progress! Reveals the mechanism by which chromatin inhibits cGAS to block autoimmune response.

September 16, 2020 /--- in advanced organisms, DNA detected in the cytoste can trigger an immune response.
enzymes that perceive "misplaced" DNA are also present in the nuclea, but cellular DNA does not have such an effect.
now, in a new study, researchers from the University of Munich in Germany report why.
results were published online September 10, 2020 in the journal Nature under the title "Structural basis for sequestration and autoinhibition of cGAS by chromatin".
-temperature electroscopic structure when cGAS (red) is combined with nuclear microsome histogene (blue), pictured is Karl-Peter Hopfner.
most of the DNA in higher biological cells is restricted to the nucleation of the cell, while all other cytogenetic DNA is restricted to the cellular chamber identified in the cytostyle.
As a result, the presence of DNA in the soluble phase of the cytostyte is interpreted by the innate immune system as a signal of the presence of in-cell pathogens ---usually bacteria or viruses--- even though tumor cells and senescies can also release nucleoblasts or mitochondrial DNA into the cytotones.
misplaced DNA --- whether from the nuclei, mitochondrials, or out-of-cell DNA --- causes a strong immune response, initiated by cGAS enzymes.
scientists have long believed that cGAS itself is located only in the cytoste.
, however, recent studies have shown that this protein actually precedes the nucleation of the cell.
finding naturally raises the question of what prevents cGAS from binding to nucleo-DNA and triggers an autoimmune response.
Now, in this new study, a team of scientists at the University of Munich's Gene Center, led by Professor Karl-Peter Hopfner, has teamed up with Professor Veit Hornung and his colleagues to reveal the nature of cGAS's interactions with chromosome DNA in the nuclei of cells and explain why they do not activate the innate immune system.
cGAS binds to the nucleo-DNA of the cell, it synthesizes a messenger molecule that triggers a cascading reaction of signals within the cell, leading to the production of proteins that mediate the inflammatory response.
process is essential to eliminate infectious pathogens.
, however, it is also associated with the production of autoimmune diseases, some of which actually involve the production of antibodies to the cell's own DNA.
therefore, the fact that cGAS is present in the nucleus does not seem to be consistent with the protective function of the innate immune system, because the activation of the enzyme itself in the nucleus leads to an autoimmune response to the nucleus DNA of the cell.
Hopfner said, "It is strange that recent data actually show that the close binding of cGAS to the DNA-protein complex ---so-chromatin--- found in the nucleus is essential to prevent DNA-based autoimmunity.
in chromosomal complexes, DNA is wrapped in disc-like particles made up of proteins called core histones.
resulting "nuclear gadgets" are connected by "linker DNA" that is not directly related to the core histogeneum.
through cryogenic electrons, Hopfner and his colleagues were able to confirm that cGAS binds only to the protein components of chromatin, not to the DNA itself.
a big surprise," said Carina de Oliveira Mannira of the University of Munich, co-author of the paper.
addition, its binding pattern ensures that the DNA identification bits of cGAS are blocked.
, even during gene activation, DNA near it can approach other proteins, and the enzyme becomes inactive in the nuclea.
, this suggests that chromatin is actually a reservoir of cGAS by trapping the enzyme in an inactive state.
" in fact, cGAS is most effectively suppressed in areas of chromatin that are less tightly wrapped, where most genes are located.
hopfner said, "This may explain why cGAS is activated in something called micronuclei in the cytoste, where chromatin is thought to be tightly wrapped."
" nucleation consists of chromosomal fragments surrounded by a nuclear membrane.
are the product of DNA damage caused by chromosomal separation errors or ionizing radiation in fast-growing tumor cells.
Hopfner said, "Our study represents an important step forward in our understanding of how cGAS interacts with chromatin.
will help us clarify the inflammatory response of this enzyme in the context of cancer and autoimmune diseases.
" (bioon.com) Reference: 1. Sebastian Michalski et al. Structural basis for sequestration and autoinhibition of cGAS by chromatin. Nature, 2020, doi:10.1038/s41586-020-2748-0.2.How cGAS enzyme is kept bottled up.