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Molecular mechanisms and cellular functions of cGAS–STING signalling

Abstract

The cGAS–STING signalling axis, comprising the synthase for the second messenger cyclic GMP–AMP (cGAS) and the cyclic GMP–AMP receptor stimulator of interferon genes (STING), detects pathogenic DNA to trigger an innate immune reaction involving a strong type I interferon response against microbial infections. Notably however, besides sensing microbial DNA, the DNA sensor cGAS can also be activated by endogenous DNA, including extranuclear chromatin resulting from genotoxic stress and DNA released from mitochondria, placing cGAS–STING as an important axis in autoimmunity, sterile inflammatory responses and cellular senescence. Initial models assumed that co-localization of cGAS and DNA in the cytosol defines the specificity of the pathway for non-self, but recent work revealed that cGAS is also present in the nucleus and at the plasma membrane, and such subcellular compartmentalization was linked to signalling specificity of cGAS. Further confounding the simple view of cGAS–STING signalling as a response mechanism to infectious agents, both cGAS and STING were shown to have additional functions, independent of interferon response. These involve non-catalytic roles of cGAS in regulating DNA repair and signalling via STING to NF-κB and MAPK as well as STING-mediated induction of autophagy and lysosome-dependent cell death. We have also learnt that cGAS dimers can multimerize and undergo liquid–liquid phase separation to form biomolecular condensates that could importantly regulate cGAS activation. Here, we review the molecular mechanisms and cellular functions underlying cGAS–STING activation and signalling, particularly highlighting the newly emerging diversity of this signalling pathway and discussing how the specificity towards normal, damage-induced and infection-associated DNA could be achieved.

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Fig. 1: Overview of canonical cGAS–STING signalling.
Fig. 2: Cellular localization and DNA ligands of cGAS.
Fig. 3: Mechanism of cGAS activation.
Fig. 4: Mechanism of STING activation.
Fig. 5: Effector functions of STING.

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Acknowledgements

The authors thank C. de Oliveira Mann and C. Stafford for discussions. The authors acknowledge support by Deutsche Forschungsgemeinschaft Grant TRR 237 (to K.-P.H. and V.H.), the Gottfried Wilhelm Leibniz-Prize (to K.-P.H. and V.H.) and by the European Reserach Council (ERC-2014-CoG – 647858 GENESIS to V.H.).

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The authors contributed equally to all aspects of the article.

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Correspondence to Karl-Peter Hopfner or Veit Hornung.

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Nature Reviews Molecular Cell Biology thanks P. Li, Z. Chen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

PDB ID 6CTA: https://www.rcsb.org/structure/6CTA

PDB ID 4KSY: https://www.rcsb.org/structure/4KSY

PDB ID 4KM5: https://www.rcsb.org/structure/4KM5

PDB ID 5N6I: https://www.rcsb.org/structure/5N6I

PDB ID 6EDB: https://www.rcsb.org/structure/6EDB

PDB ID 6NT6: https://www.rcsb.org/structure/6NT6

PDB ID 6NT7: https://www.rcsb.org/structure/6NT7

Glossary

Innate immune system

A heterogeneous system of molecules, signal transducers and cells that has evolved to detect invading microbes, and elicits a first line of antimicrobial defence and activates the adaptive immune system.

Pattern recognition receptors

(PPRs). Germline-encoded receptors of the innate immune system. They detect pathogen or danger/damage-associated molecular patterns and elicit cellular defence reactions.

Pathogen and damage-associated molecular patterns

(PAMPs and DAMPs). Molecules that signal the presence of pathogens (that is, PAMPs) or danger/damage (that is, DAMPs). They are recognized by pattern recognition receptors.

Adaptive immune system

A branch of the immune system that comprises B and T lymphocytes. It elicits a highly specific response to antigens through highly variable, clonally expressed B cell receptors/antibodies or T cell receptors.

Nucleotidyl transferase

(NTase). A class of enzymes that transfer nucleoside phosphates onto an acceptor, typically a hydroxyl group.

Cyclic dinucleotide

Two nucleoside phosphates, joined in a circular dinucleotide through two phosphodiester linkages. Cyclic dinucleotides are found in prokaryotes and higher eukaryotes, and typically have second messenger functions to regulate diverse activities, such as bacterial biofilm and planktonic lifestyles (c-di-GMP), osmolyte homeostasis (c-di-AMP) and eukaryotic innate immune signalling (cyclic GMP–AMP).

Cellular senescence

A state that is generally characterized by a permanent cell cycle arrest in the context of ageing or tumour suppression. It can be promoted by multiple factors, including oxidative stress, DNA damage, mitochondrial dysfunction and the unfolded protein response.

Aicardi–Goutières syndrome

A rare, genetically determined progressive encephalopathy with autoimmune features that is caused by mutations in various genes involved in nucleic acid metabolism.

Systemic lupus erythematosus

A systemic, chronic, autoimmune disease that affects connective tissue of the kidneys, heart, lungs, brain, blood and skin.

Liquid–liquid phase separation

In cell biology, the separation of macromolecules (proteins, nucleic acids) into two liquid-like phases with high and low concentrations of the macromolecule.

Major histocompatibility complex class II

(MHC II). Surface molecules, typically found on antigen presenting cells such as dendritic cells, macrophages and B cells, that display peptides derived from extracellular proteins for interaction with immune cells.

Dendritic cells

Specialized antigen-presenting cells in a heterogeneous group that act as a link between the innate and adaptive immune system. They take up and process antigens and induce naive T lymphocyte activation and effector cell differentiation.

Extracellular vesicles

Secreted vesicles produced by many cell types, including tumour cells that can carry a wide variety of cellular components, including DNA, RNA, proteins and other molecules. They include two main subpopulations known as microvesicles and exosomes that differ in their mode of biogenesis (plasma membrane versus endosomal origin).

Natural killer cells

Cytotoxic effector lymphocytes of the innate immune system that play critical roles in antitumour and antimicrobial defence.

BAK/BAX macropores

Pores in the outer membrane of mitochondria, formed by the BAK and BAX proteins to trigger cytochrome c release and apoptosis.

Effector caspases

Proteinases activated through cleavage by initiator caspases (caspase cascade) that then proteolytically cleave many target proteins to execute apoptosis.

Mitochondrial stress

Pathophysiological conditions leading to mitochondrial DNA stress, mitochondrial unfolded protein response and stress signalling pathways.

Nucleosomal arrays

Sequences of regularly spaced nucleosomes along the DNA, typically found at gene bodies of eukaryotic chromosomes.

Nucleosome core particles

Histone protein octamers together with ~147 bp of tightly wrapped DNA, which is protected from nuclease digestion.

Linker DNA

DNA connecting two adjacent nucleosome core particles. This can range in length in different species, cell types and loci.

Nuclear envelope blebbing

The formation of membrane bulges at the nuclear envelope. At these sites, the membrane separates from the underlying lamina, allowing the chromatin to herniate and protrude into the bleb. In the event of membrane rupture, blebbing results in exchanging material between cytosol and nucleoplasm.

Telomeres

Specialized protective end structures of linear chromosomes, consisting of a repetitive DNA sequence and associated proteins.

Senescence-associated cell cycle arrest

The shortening of telomeres leading to a prolonged DNA damage response and check-point activation to trigger a permanent cell cycle arrest, a hallmark of senescent cells.

Dicentric chromosomes

Chromosomes containing two centromeres formed through genome rearrangements.

Alternative lengthening of telomeres

(ALT). The telomerase-independent, recombination-dependent mode of extension of telomeres in cancer cells.

Autophagy

A regulated system in which the cell degrades unwanted cellular components by incorporation into autophagosomes followed by fusion with lysosomes.

γ-H2AX

The phosphorylation of histone 2A variant X at Ser139, leading to nucleosomes containing γ-H2AX. This mark is an early cellular response to DNA double-strand breaks, which serves in the recruitment of other repair factors.

Poly-ADP ribose polymerase 1

(PARP1). An enzyme that binds and marks DNA breaks by adding poly-ADP-ribose (PAR) onto itself and other targets.

LINE1

(Long interspersed nuclear element 1). A class I transposable element, typically 6 kb long, present in the genome of humans and some other organisms. LINE1 elements comprise around 17% of the human genome.

Homologous recombination

A DNA double-strand break repair pathway in which a DNA end is resected, and the resulting single-strand is extended on a homologous template

Gap junctions

Specialized cell–cell channels formed by juxtaposed connexon pores of adjacent cells, allowing the cytoplasmic exchange of small molecules and ions.

TIMELESS

A protein implicated in the circadian rhythm, replication and enhancing homologous recombination through interactions with different proteins.

Non-homologous end-joining

A DNA double-strand break repair pathway in which two DNA ends are directly ligated, often after limited processing by nucleases and DNA polymerases, in a pathway that depends on DNA-dependent protein kinase and DNA ligase IV.

COPII coat complex

A protein complex in the secretory pathway composed of five proteins that coats membrane vesicles transporting material from the endoplasmic reticulum to the Golgi apparatus.

ER–Golgi intermediate compartment

(ERGIC). An organellar structure that mediates trafficking between the endoplasmic reticulum (ER) and the Golgi apparatus.

Palmitoylation

A lipid modification of proteins through covalent attachment of palmitic acid, regulating different properties of proteins, such as membrane interaction, stability and trafficking.

MAPK

A type of protein kinase that transduces extracellular signals, such as growth factors, cytokines and mitogens, to cellular programmes, such as growth, differentiation, inflammation and others.

LC3

(Also known as microtubule-associated proteins 1A/1B light chain 3B). A protein that functions in substrate selection in autophagy and is used as a marker for autophagosomes.

SAVI

(STING-associated vasculopathy with onset in infancy). A rare autoinflammatory vasculopathy characterized by severe skin lesions and interstitial lung disease.

NLRP3 inflammasome

A multiprotein complex that initiates a pro-inflammatory cell death with the release of IL-1β in response to activation by NLRP3, which senses microbial and endogenous danger signals.

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Hopfner, KP., Hornung, V. Molecular mechanisms and cellular functions of cGAS–STING signalling. Nat Rev Mol Cell Biol 21, 501–521 (2020). https://doi.org/10.1038/s41580-020-0244-x

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