Magic! On the same day, Nature published three papers on cGAS, and Science published two cGAS papers that revealed the mechanism by which nuclear gadgets bind to inhibit cGAS to block autoimmune responses.

!--webeditor: page title" -- September 23, 2020 / / most of the DNA in the higher biological cells of --- is restricted to the nuclei of the cells, while all other cytogenetic DNA is restricted to the cellular chambers 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.
in all mammals, cyclic GMP-AMP comptase (cGAS) senses the invasion of pathogenIC DNA and stimulates inflammatory signal transductivity, autophagy, and apoptosis.
cGAS works by detecting DNA in the wrong place.
under normal conditions, DNA is tightly packed in the nucleation and protected.
there is no reason for DNA to move freely around cells.
When DNA fragments do eventually escape the nucleus and enter the cytoste, this usually indicates some ominous signs, such as damage from within the cell or foreign DNA from viruses or bacteria that invade the cell.
cGAS protein works by identifying this DNA in the wrong place.
under normal circumstances, it is dormant in the cell.
but once cGAS detects that DNA is outside the nuclea, it suddenly works.
it produces another chemical--- a second messenger called 2'3' ring GMP-AMP (cGAMP), which triggers a molecular chain reaction that alerts cells to DNA abnormalities.
at the end of this signal cascading reaction, the cells are either repaired or damaged to the point where they cannot be repaired, it destroys itself.
but the health and integrity of cells depends on cGAS being able to distinguish harmless DNA from foreign DNA or their own DNA released during cell damage and stress.
shows that cGAS plays a very important role in mammals, including humans.
September 10, 2020, nature and Science published three and two papers on cGAS, respectively, and both related to the structure of cGAS.
next, let's find out.
1.Nature: The nucleic acids that reveal the molecular basis of nucleosome binding leading to cGAS insisnia doi:10.1038/s41586-020-2749-z pathogen sources can induce a strong innate immune response.
-ring GMP-AMP heteroenzyme (cGAS) is a double-stranded DNA (dsDNA) sensing protein that catalyzes the synthesis of ring-shaped d-nucleotide cGAMP, resulting in cGAMP induced by STING-TBK1-IRF3 signal axis-mediated type I interferon.
cGAS is present in the cytotyte and it is widely accepted that it is not reactive to its own DNA.
, however, recent studies have shown that cGAS is mainly present in the nucleus of cells, and that tight nucleosome bondage keeps cGAS inactive.
a new study, researchers from Texas Agricultural University in the United States found that cGAS binds nuclear small bodies with nanomolar affinity, and that nuclear small body binding strongly inhibits the catalytic activity of cGAS.
to clarify the molecular basis for cGAS inseption caused by nuclear small body binding, they determined the cryogenic electroscope (cryo-EM) structure in mice when cGAS is combined with human nuclear small bodies.
results were published online September 10, 2020 in the journal Nature under the title "The Molecular Basis of Tight Nuclear Tethering and Inactivation of cGAS".
image from Frontiers in Immunology, 2018, doi:10.3389/fimmu.2018.01297.
this structure indicates that cGAS binds to negatively charged acidic pockets (acid patches) formed by hismoglobins H2A and H2B through its second DNA binding bit.
high-affinity nucleosome binding prevents dsDNA binding and leaves cGAS in an inactive configuration.
cGAS mutations that destroy the binding of nuclear gadgets greatly affect the signal transductivity of cGAS-mediated cells.
2. Nature: Revealing the structural mechanism of nuclear small bodies inhibiting cGAS doi:10.1038/s41586-020-2750-6 In a new study, researchers from the Federal Institute of Technology in Lausanne, Switzerland, and the University of Basel identified a cryogenic electron (cryo-EM) structure with a resolution of 3.1 E when combined with nuclear small bodies.
results were published online September 10, 2020 in the journal Nature under the title "Structural mechanism of cGAS resedion by the nucleosome".
cGAS is widely exposed to acidic pockets (acid patches) and nucleosome DNA of histogeneic H2A-H2B heterogeneums.
structure and complementary bio-chemical analysis also found that cGAS and the second nuclear small body trans-combination.
the mechanism, nuclear small body binding locks cGAS in a monogasic state, in which spatial bit resistance inhibits the wrong activation of genomic DNA to cGAS.
the researchers found that mutations in the cGAS-acid pocket interface were sufficient to eliminate the inhibition of cGAS by nucleosomes in introphy and to trigger the enzyme activity of cGAS in genomic DNA in living cells.
study sheds light on the structural basis for cGAS interactions with chromatin and identifies a compelling mechanism that allows cGAS to self-identify genomic DNA.
!--/ewebeditor:page--!--ewebeditor:page-title"--3.Science: Revealing the structural basis of nucleosome suppression cGAS activation doi:10.1126/science.abd0237 Some people suggest that the host DNA assembly into a nucleosome can limit the automatic activation of cGAS, but its basic mechanism is not clear.
study, researchers from the University of Tokyo, Waseda University and Rockefeller University in the United States reported the structural basis for this inhibition.
results were published online September 10, 2020 in the journal Science under the title "Structural basis for the resedion of the cGAS by nucleosomes".
high-resolution structure when the protein cGAS (blue-green, top) is combined with the nucleosome, pictured from UNC-Chapel Hill.
the researchers analyzed the cryo-EM structure of the human cGAS-nuclear small core particle (cGAS-NCP) complex.
in this structure, two cGAS monosomes bridge two nucleosome core particles (NCP) by combining H2A-H2B acidic pockets (acid patches) and nucleosome DNA.
in this configuration, all three known cGAS DNA binding bits required for cGAS activation are reused or inconn accessed, and cGAS djuogeneity is suppressed as another prerequisite for cGAS activation.
mutations in key amino acid residues that connect the acidic pockets of cGAS to H2A-H2B can reduce the inhibition of cGAS activation in the nucleosome.
, the new study establishes a structural framework that explains why cGAS is inhibited in chromatin-stained self-DNA.
4. Science: In a new study, researchers at the University of North Carolina at Chapel Hill identified for the first time a high-resolution structure in the congenital immune system in which a key DNA-sensing protein called cGAS binds to a nucleosome, where the nucleosome is the most important DNA packaging unit in the nucleus.
results were published online September 10, 2020 in the journal Science under the title "Structural basis of nucleosome-dependent cGAS resedion".
study details how nucleosomes in our cells prevent cGAS from inadvertently triggering the body's innate immune response to its own DNA.
the paper is co-authored by Dr. Qi Zhang, Associate Professor of Biochemistry and Biophysics, Faculty of Medicine, University of North Carolina at Chapel Hill, and Dr. Robert McGinty, Assistant Professor of Chemical Biology and Pharmaceutical Chemistry, Esherman School of Pharmacy, University of North Carolina, Chapel Hill.
using the state-of-the-art frozen electroscope core facility at the University of North Carolina at Chapel Hill School of Medicine, established in 2019, Zhang and McGinty Labs identified a 3.3-E resolution frozen electromirror structure when cGAS is combined with a nuclear microsome.
this structure shows that cGAS uses two conservative amino acids to anchor on a negatively charged acidic pocket (acid patch) on the surface of the nucleosome.
these protein-protein interactions allow the nucleosome to occupy a key DNA sensing surface on cGAS and prevent cGAS from entering its functionally active DNA binding state.
combined with mutation and functional assays, this study describes how cGAS maintains a stationary, inhibitory state in the nucleus at near-atomic resolution.
.Nature: Significant progress! Revealed chromatin inhibition cGAS thus blocking autoimmune response mechanism doi:10.1038/s41586-020-2748-0 In advanced organisms, DNA in the cytotyte is detected to 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.
in the new study, a team of scientists at the University of Munich's Gene Center, led by Professor Karl-Peter Hopfner, teamed up with Professor Veit Hornung and colleagues to reveal the nature of cGAS's interactions with chromosomal DNA in the nucleosome 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. <