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DNA sensing by the cGAS–STING pathway in health and disease

Nature Reviews Genetics volume 20, pages 657–674 (2019)Cite this article

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Abstract

The detection of pathogens through nucleic acid sensors is a defining principle of innate immunity. RNA-sensing and DNA-sensing receptors sample subcellular compartments for foreign nucleic acids and, upon recognition, trigger immune signalling pathways for host defence. Over the past decade, our understanding of how the recognition of nucleic acids is coupled to immune gene expression has advanced considerably, particularly for the DNA-sensing receptor cyclic GMP–AMP synthase (cGAS) and its downstream signalling effector stimulator of interferon genes (STING), as well as the molecular components and regulation of this pathway. Moreover, the ability of self-DNA to engage cGAS has emerged as an important mechanism fuelling the development of inflammation and implicating the cGAS–STING pathway in human inflammatory diseases and cancer. This detailed mechanistic and biological understanding is paving the way for the development and clinical application of pharmacological agonists and antagonists in the treatment of chronic inflammation and cancer.

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Fig. 1: DNA-sensing receptors.
Fig. 2: The cGAS–STING DNA-sensing pathway.
Fig. 3: cGAS–STING-mediated autoimmunity.
Fig. 4: Balancing the roles of the cGAS–STING pathway activation and inhibition in cancer.

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Acknowledgements

The authors apologize to authors whose work was not discussed or cited owing to space limitations. This work was supported by grants from the Lupus Research Alliance and the NIH (AI067497, AI079293 and AI128358).

Author information

Authors and Affiliations

  1. Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA

    Mona Motwani & Katherine A. Fitzgerald

  2. Innate Immunity Research Unit, GlaxoSmithKline, Collegeville, PA, USA

    Scott Pesiridis

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  1. Mona Motwani
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  2. Scott Pesiridis
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All authors contributed equally to this manuscript.

Corresponding author

Correspondence to Katherine A. Fitzgerald.

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Competing interests

S.P. is an Associate GlaxoSmithKline Fellow and Research Leader at GlaxoSmithKline. K.A.F. has received funding and previous consulting fees from GlaxoSmithKline related to nucleic acid sensing pathways. M.M. declares no competing interests.

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Nature Reviews Genetics thanks Y. Crow, S. Bakhoum, Z. Jiang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Pattern recognition receptors

Germline-encoded receptors that detect pathogen-associated molecular patterns (microbial products).

Cyclic dinucleotides

A class of nucleic-acid second messenger molecules that typically contain two mononucleotides connected by a unique phosphodiester linkage, such as cyclic 2′-5′,3′-5′ adenine monophosphate guanine monophosphate linkages in human cyclic GMP–AMP.

Pyroptosis

A caspase 1/11-dependent inflammatory cell death process.

Necroptosis

A receptor-interacting serine/threonine-protein kinase (RIPK)-dependent programmed cell death pathway.

Mitophagy

An autophagic process in response to cellular damage or stress during which mitochondria are degraded.

Phosphodiesterases

Enzymes that break phosphodiester bonds in cyclic dinucleotides.

Endogenous retroelements

Genes that can integrate anywhere into the human genome, often referred to as mobile genetic elements; endogenous retroelements arise from integration of retroviruses into human genomes.

Antinuclear antibodies

During autoimmunity, these antibodies are made against self-proteins such as histones, nucleosomes or DNA.

Systemic lupus erythematosus

An autoimmune disorder in which the immune system aberrantly attacks host tissues.

Merotelic kinetochores

Kinetochores arranged in a merotelic orientation, whereby one kinetochore is attached to opposing spindle poles.

Breakage–fusion–bridge cycle

A process whereby broken chromosomes fuse with other broken chromosomes that segregate to opposite spindle poles during mitosis, forming the chromosome bridge; the bridge is consequently broken during mitosis, instigating a cyclic pattern of chromosomal breakage and fusion that propagates chromosome instability.

Chromosome instability

A type of genomic instability in which chromosomes are unstable, such that either whole chromosomes or parts of chromosomes are duplicated or deleted.

Chromothripsis

A cellular description of asynchronous chromosome condensation coincident with a high frequency of chromosomal rearrangements condensed to a specific region of a chromosome.

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Motwani, M., Pesiridis, S. & Fitzgerald, K.A. DNA sensing by the cGAS–STING pathway in health and disease. Nat Rev Genet 20, 657–674 (2019). https://doi.org/10.1038/s41576-019-0151-1

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