Structural basis for sequestration and autoinhibition of cGAS by chromatin.

Abstract:

:Cyclic GMP-AMP synthase (cGAS) is an innate immune sensor for cytosolic microbial DNA1. After binding DNA, cGAS synthesizes the messenger 2'3'-cyclic GMP-AMP (cGAMP)2-4, which triggers cell-autonomous defence and the production of type I interferons and pro-inflammatory cytokines via the activation of STING5. In addition to responding to cytosolic microbial DNA, cGAS also recognizes mislocalized cytosolic self-DNA and has been implicated in autoimmunity and sterile inflammation6,7. Specificity towards pathogen- or damage-associated DNA was thought to be caused by cytosolic confinement. However, recent findings place cGAS robustly in the nucleus8-10, where tight tethering of chromatin is important to prevent autoreactivity to self-DNA8. Here we show how cGAS is sequestered and inhibited by chromatin. We provide a cryo-electron microscopy structure of the cGAS catalytic domain bound to a nucleosome, which shows that cGAS does not interact with the nucleosomal DNA, but instead interacts with histone 2A-histone 2B, and is tightly anchored to the 'acidic patch'. The interaction buries the cGAS DNA-binding site B, and blocks the formation of active cGAS dimers. The acidic patch robustly outcompetes agonistic DNA for binding to cGAS, which suggests that nucleosome sequestration can efficiently inhibit cGAS, even when accessible DNA is nearby, such as in actively transcribed genomic regions. Our results show how nuclear cGAS is sequestered by chromatin and provides a mechanism for preventing autoreactivity to nuclear self-DNA.

journal_name

Nature

journal_title

Nature

authors

Michalski S,de Oliveira Mann CC,Stafford CA,Witte G,Bartho J,Lammens K,Hornung V,Hopfner KP

doi

10.1038/s41586-020-2748-0

subject

Has Abstract

pub_date

2020-11-01 00:00:00

pages

678-682

issue

7835

eissn

0028-0836

issn

1476-4687

pii

10.1038/s41586-020-2748-0

journal_volume

587

pub_type

杂志文章

相关文献

NATURE文献大全
  • The changing face of HIV in China.

    abstract::HIV has advanced from high-risk groups such as intravenous drug users to some in the general population, according to comprehensive new data from the south of China. What needs to be done to halt its spread? ...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/455609a

    authors: Lu L,Jia M,Ma Y,Yang L,Chen Z,Ho DD,Jiang Y,Zhang L

    更新日期:2008-10-02 00:00:00

  • Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers.

    abstract::Highly rearranged and mutated cancer genomes present major challenges in the identification of pathogenetic events driving the neoplastic transformation process. Here we engineered lymphoma-prone mice with chromosomal instability to assess the usefulness of mouse models in cancer gene discovery and the extent of cross...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature05886

    authors: Maser RS,Choudhury B,Campbell PJ,Feng B,Wong KK,Protopopov A,O'Neil J,Gutierrez A,Ivanova E,Perna I,Lin E,Mani V,Jiang S,McNamara K,Zaghlul S,Edkins S,Stevens C,Brennan C,Martin ES,Wiedemeyer R,Kabbarah O,Noguei

    更新日期:2007-06-21 00:00:00

  • Publisher Correction: In vivo imaging of mitochondrial membrane potential in non-small-cell lung cancer.

    abstract::An Amendment to this paper has been published and can be accessed via a link at the top of the paper. ...

    journal_title:Nature

    pub_type: 杂志文章,已发布勘误

    doi:10.1038/s41586-019-1890-z

    authors: Momcilovic M,Jones A,Bailey ST,Waldmann CM,Li R,Lee JT,Abdelhady G,Gomez A,Holloway T,Schmid E,Stout D,Fishbein MC,Stiles L,Dabir DV,Dubinett SM,Christofk H,Shirihai O,Koehler CM,Sadeghi S,Shackelford DB

    更新日期:2020-01-01 00:00:00

  • Leukotriene B, a potent chemokinetic and aggregating substance released from polymorphonuclear leukocytes.

    abstract::Arachidonic acid is metabolised either by cyclooxygenases to produce prostaglandins and thromboxanes or by lipoxygenases to produce mono-, di- and trihydroxyeicosatetraenoic acids (HETEs). Polymorphonuclear leukocytes (PMNs) release HETEs, including mono- and dihydroxy fatty acids, when exposed to stimuli such as the ...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/286264a0

    authors: Ford-Hutchinson AW,Bray MA,Doig MV,Shipley ME,Smith MJ

    更新日期:1980-07-17 00:00:00

  • Sirtuin activators mimic caloric restriction and delay ageing in metazoans.

    abstract::Caloric restriction extends lifespan in numerous species. In the budding yeast Saccharomyces cerevisiae this effect requires Sir2 (ref. 1), a member of the sirtuin family of NAD+-dependent deacetylases. Sirtuin activating compounds (STACs) can promote the survival of human cells and extend the replicative lifespan of ...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature02789

    authors: Wood JG,Rogina B,Lavu S,Howitz K,Helfand SL,Tatar M,Sinclair D

    更新日期:2004-08-05 00:00:00

  • Formation of olfactory memories mediated by nitric oxide.

    abstract::Sheep learn to recognize the odours of their lambs within two hours of giving birth, and this learning involves synaptic changes within the olfactory bulb. Specifically, mitral cells become increasingly responsive to the learned odour, which stimulates release of both glutamate and GABA (gamma-aminobutyric acid) neuro...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/41765

    authors: Kendrick KM,Guevara-Guzman R,Zorrilla J,Hinton MR,Broad KD,Mimmack M,Ohkura S

    更新日期:1997-08-14 00:00:00

  • Spontaneous sign systems created by deaf children in two cultures.

    abstract::Deaf children whose access to usable conventional linguistic input, signed or spoken, is severely limited nevertheless use gesture to communicate. These gestures resemble natural language in that they are structured at the level both of sentence and of word. Although the inclination to use gesture may be traceable to ...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/34646

    authors: Goldin-Meadow S,Mylander C

    更新日期:1998-01-15 00:00:00

  • Origin of luteinizing hormone-releasing hormone neurons.

    abstract::Neurons expressing luteinizing hormone-releasing hormone (LHRH), found in the septal-preoptic nuclei and hypothalamus, control the release of gonadotropic hormones from the anterior pituitary gland and facilitate reproductive behaviour. LHRH-expressing neurons are also found in the nervus terminalis, a cranial nerve t...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/338161a0

    authors: Schwanzel-Fukuda M,Pfaff DW

    更新日期:1989-03-09 00:00:00

  • Paramyxovirus SV5 and multiple sclerosis.

    abstract::Multiple sclerosis is commonly associated with a local humoral immune response within the central nervous system. A hallmark of this intrathecal response is the presence of electrophoretically demonstrable oligoclonal bands of IgG in the cerebrospinal fluid (CSF) of up to 95% of patients. Observations indicating that ...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/338769a0

    authors: Vandvik B,Norrby E

    更新日期:1989-04-27 00:00:00

  • Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean.

    abstract::Members of the muscarinic acetylcholine receptor family (M1-M5) have central roles in the regulation of many fundamental physiological functions. Identifying the specific receptor subtype(s) that mediate the diverse muscarinic actions of acetylcholine is of considerable therapeutic interest, but has proved difficult p...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/35065604

    authors: Yamada M,Miyakawa T,Duttaroy A,Yamanaka A,Moriguchi T,Makita R,Ogawa M,Chou CJ,Xia B,Crawley JN,Felder CC,Deng CX,Wess J

    更新日期:2001-03-08 00:00:00

  • Targeted misexpression of a Drosophila opsin gene leads to altered visual function.

    abstract::Drosophila mutants transformed with a chimaeric gene that expresses the ocellar visual pigment in the major class of photoreceptor cells of the retina were used to investigate the properties of this minor pigment. The photoreceptor cells in which this opsin was misexpressed showed new spectral characteristics and phys...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/333737a0

    authors: Feiler R,Harris WA,Kirschfeld K,Wehrhahn C,Zuker CS

    更新日期:1988-06-23 00:00:00

  • A short timescale for terrestrial planet formation from Hf-W chronometry of meteorites.

    abstract::Determining the chronology for the assembly of planetary bodies in the early Solar System is essential for a complete understanding of star- and planet-formation processes. Various radionuclide chronometers (applied to meteorites) have been used to determine that basaltic lava flows on the surface of the asteroid Vest...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature00995

    authors: Yin Q,Jacobsen SB,Yamashita K,Blichert-Toft J,Télouk P,Albarède F

    更新日期:2002-08-29 00:00:00

  • Bcl-2 promotes regeneration of severed axons in mammalian CNS.

    abstract::Most neurons of the mammalian central nervous system (CNS) lose the ability to regenerate severed axons in vivo after a certain point in development. At least part of this loss in regenerative potential is intrinsic to neurons. Although embryonic retinal ganglion cells (RGCs) can grow axons into tectum of any age, mos...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/385434a0

    authors: Chen DF,Schneider GE,Martinou JC,Tonegawa S

    更新日期:1997-01-30 00:00:00

  • Hydrolytic stability of biomolecules at high temperatures and its implication for life at 250 degrees C.

    abstract::The upper temperature at which a living system can exist is limited by the hydrolytic breakdown rate of its chemical constituents. The peptide bonds of proteins, the phosphodiester and N-glycosyl bonds in RNA and DNA, and the pyrophosphate and N-glycosyl bonds in nucleotides such as ATP and NAD are among the more impo...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/310430a0

    authors: White RH

    更新日期:1984-08-02 00:00:00

  • Structural invariants in protein folding.

    abstract::An analysis of 15 protein structures indicates: First, the loss of accessible surface area by monomeric proteins on folding-proportional to hydrophobic energy-is a simple function of molecular weight; second, the proportion of polar groups forming intramolecular hydrogen bonds is constant; and third, protein interiors...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/254304a0

    authors: Chothia C

    更新日期:1975-03-27 00:00:00

  • Oceanic forcing of penultimate deglacial and last interglacial sea-level rise.

    abstract::Sea-level histories during the two most recent deglacial-interglacial intervals show substantial differences1-3 despite both periods undergoing similar changes in global mean temperature4,5 and forcing from greenhouse gases6. Although the last interglaciation (LIG) experienced stronger boreal summer insolation forcing...

    journal_title:Nature

    pub_type: 历史文章,杂志文章

    doi:10.1038/s41586-020-1931-7

    authors: Clark PU,He F,Golledge NR,Mitrovica JX,Dutton A,Hoffman JS,Dendy S

    更新日期:2020-01-01 00:00:00

  • Expression pattern of zebrafish pax genes suggests a role in early brain regionalization.

    abstract::In vertebrates the developing hindbrain is organized in segmental units. These units provide the primary grid for differentiation and axonal outgrowth. In the more anterior regions of the brain, however, the subdivisions remain more controversial. Cellular and molecular studies of the embryonic brain in lower vertebra...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/353267a0

    authors: Krauss S,Johansen T,Korzh V,Fjose A

    更新日期:1991-09-19 00:00:00

  • Molecular recognition of a single sphingolipid species by a protein's transmembrane domain.

    abstract::Functioning and processing of membrane proteins critically depend on the way their transmembrane segments are embedded in the membrane. Sphingolipids are structural components of membranes and can also act as intracellular second messengers. Not much is known of sphingolipids binding to transmembrane domains (TMDs) of...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature10742

    authors: Contreras FX,Ernst AM,Haberkant P,Björkholm P,Lindahl E,Gönen B,Tischer C,Elofsson A,von Heijne G,Thiele C,Pepperkok R,Wieland F,Brügger B

    更新日期:2012-01-09 00:00:00

  • Control of grip and stick in cell adhesion through lateral relationships of membrane glycoproteins.

    abstract::Although cell adhesion to substrate must ultimately depend on 'sticking' by physical forces at the outer surface, we suggest that control is exercised through the 'grip' of the cytoskeleton. Our experiments indicate that grip can be relaxed by agents which release surface glycoproteins from some form of side-to-side o...

    journal_title:Nature

    pub_type: 杂志文章,评审

    doi:10.1038/267124a0

    authors: Rees DA,Lloyd CW,Thom D

    更新日期:1977-05-12 00:00:00

  • Magnetic trapping of neutrons

    abstract::Accurate measurement of the lifetime of the neutron (which is unstable to beta decay) is important for understanding the weak nuclear force and the creation of matter during the Big Bang. Previous measurements of the neutron lifetime have mainly been limited by certain systematic errors; however, these could in princi...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/47444

    authors: Huffman PR,Brome CR,Butterworth JS,Coakley KJ,Dewey MS,Dzhosyuk SN,Golub R,Greene GL,Habicht K,Lamoreaux SK,Mattoni CE,McKinsey DN,Wietfeldt FE,Doyle JM

    更新日期:2000-01-06 00:00:00

  • Molecular analysis of spontaneous somatic mutants.

    abstract::Eukaryotic structural gene mutations occurring spontaneously in a mouse myeloma cell line offer the opportunity to study somatic mutation in animal cells at the molecular level. Studies on the myeloma protein and on mRNA have enabled us to characterise four such mutants representing four different mutation mechanisms....

    journal_title:Nature

    pub_type: 杂志文章,评审

    doi:10.1038/265299a0

    authors: Adetugbo K,Milstein C,Secher DS

    更新日期:1977-01-27 00:00:00

  • L1 retrotransposition in neurons is modulated by MeCP2.

    abstract::Long interspersed nuclear elements-1 (LINE-1 or L1s) are abundant retrotransposons that comprise approximately 20% of mammalian genomes. Active L1 retrotransposons can impact the genome in a variety of ways, creating insertions, deletions, new splice sites or gene expression fine-tuning. We have shown previously that ...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature09544

    authors: Muotri AR,Marchetto MC,Coufal NG,Oefner R,Yeo G,Nakashima K,Gage FH

    更新日期:2010-11-18 00:00:00

  • Guard cell abscisic acid signalling and engineering drought hardiness in plants.

    abstract::Guard cells are located in the epidermis of plant leaves, and in pairs surround stomatal pores. These control both the influx of CO2 as a raw material for photosynthesis and water loss from plants through transpiration to the atmosphere. Guard cells have become a highly developed system for dissecting early signal tra...

    journal_title:Nature

    pub_type: 杂志文章,评审

    doi:10.1038/35066500

    authors: Schroeder JI,Kwak JM,Allen GJ

    更新日期:2001-03-15 00:00:00

  • Magnetic-field-induced superconductivity in a two-dimensional organic conductor.

    abstract::The application of a sufficiently strong magnetic field to a superconductor will, in general, destroy the superconducting state. Two mechanisms are responsible for this. The first is the Zeeman effect, which breaks apart the paired electrons if they are in a spin-singlet (but not a spin-triplet) state. The second is t...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/35073531

    authors: Uji S,Shinagawa H,Terashima T,Yakabe T,Terai Y,Tokumoto M,Kobayashi A,Tanaka H,Kobayashi H

    更新日期:2001-04-19 00:00:00

  • Axonal transport of vasoactive intestinal peptide in sciatic nerve.

    abstract::Dense plexuses of neurones containing immunoreactive vasoactive intestinal peptide (VIP) have been found in discrete areas of the central nervous system and in peripheral organs, including the gastrointestinal tract, pancreas and urogenital system. In many of these locations VIP is concentrated in nerve endings, where...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/281574a0

    authors: Giachetti A,Said SI

    更新日期:1979-10-18 00:00:00

  • Clustering of voltage-dependent sodium channels on axons depends on Schwann cell contact.

    abstract::In myelinated nerves, segregation of voltage-dependent sodium channels to nodes of Ranvier is crucial for saltatory conduction along axons. As sodium channels associate and colocalize with ankyrin at nodes of Ranvier, one possibility is that sodium channels are recruited and immobilized at axonal sites which are speci...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/356333a0

    authors: Joe EH,Angelides K

    更新日期:1992-03-26 00:00:00

  • The mitochondrial calcium uniporter is a highly selective ion channel.

    abstract::During intracellular Ca2+ signalling mitochondria accumulate significant amounts of Ca2+ from the cytosol. Mitochondrial Ca2+ uptake controls the rate of energy production, shapes the amplitude and spatio-temporal patterns of intracellular Ca2+ signals, and is instrumental to cell death. This Ca2+ uptake is undertaken...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature02246

    authors: Kirichok Y,Krapivinsky G,Clapham DE

    更新日期:2004-01-22 00:00:00

  • Mastering Atari, Go, chess and shogi by planning with a learned model.

    abstract::Constructing agents with planning capabilities has long been one of the main challenges in the pursuit of artificial intelligence. Tree-based planning methods have enjoyed huge success in challenging domains, such as chess1 and Go2, where a perfect simulator is available. However, in real-world problems, the dynamics ...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/s41586-020-03051-4

    authors: Schrittwieser J,Antonoglou I,Hubert T,Simonyan K,Sifre L,Schmitt S,Guez A,Lockhart E,Hassabis D,Graepel T,Lillicrap T,Silver D

    更新日期:2020-12-01 00:00:00

  • Ecological and evolutionary processes at expanding range margins.

    abstract::Many animals are regarded as relatively sedentary and specialized in marginal parts of their geographical distributions. They are expected to be slow at colonizing new habitats. Despite this, the cool margins of many species' distributions have expanded rapidly in association with recent climate warming. We examined f...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/35079066

    authors: Thomas CD,Bodsworth EJ,Wilson RJ,Simmons AD,Davies ZG,Musche M,Conradt L

    更新日期:2001-05-31 00:00:00

  • Are U4 small nuclear ribonucleoproteins involved in polyadenylation?

    abstract::The mechanism whereby eukaryotic pre-messenger RNAs are polyadenylated is unknown. Most models for polyadenylation invoke cleavage of precursor transcripts at the site of poly(A) addition followed by polymerization of A residues by poly(A) polymerase. Analysis of the sequences surrounding poly(A) addition sites has id...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/309179a0

    authors: Berget SM

    更新日期:1984-05-10 00:00:00