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Intracellular DNA recognition

Nature Reviews Immunology volume 10, pages 123–130 (2010)Cite this article

Subjects

Key Points

  • Nucleic acids derived from microorganisms or dying host cells are recognized by Toll-like receptor 7 (TLR7), TLR8 and TLR9 in endo-lysosomal compartments. In the cytoplasm, there are several distinct mechanisms for nucleic acid recognition.

  • Cytoplasmic DNA from microorganisms or delivered by transfection can trigger two main responses. First, cytoplasmic DNA activates a transcriptional response leading to the activation of nuclear factor-κB (NF-κB) and interferon regulatory factor 3 (IRF3) and the subsequent production of pro-inflammatory cytokines and type I interferons (IFNs). Second, cytoplasmic DNA triggers a proteolytic cascade leading to the activation of interleukin-1β (IL-1β) family cytokines.

  • The transcriptional response to cytoplasmic DNA is triggered by DNA-dependent activator of IRFs (DAI) and potentially other DNA sensors, leading to the initiation of a signalling pathway that involves stimulator of IFN genes (STING) and IRF3. Another DNA-sensing pathway that leads to gene induction is enabled by RNA polymerase III, which transcribes AT-rich double-stranded DNA (dsDNA) into 5′ triphosphate dsRNA. The generated RNA activates the retinoic acid-inducible gene I (RIG-I) pathway. This pathway is functional, but redundant, in mouse cells.

  • Cytoplasmic DNA induces the PYHIN family protein AIM2 (absent in melanoma 2) to form an inflammasome together with ASC (apoptosis-related speck-like protein). The induction of the AIM2 inflammasome leads to the activation of caspase-1, which in turn cleaves and activates pro-IL-1β and pro-IL-18.

  • The signalling pathways induced by cytoplasmic DNA are better understood than the receptors that are involved in activating these pathways. AT-rich dsDNA and dsDNA of random sequence activate partially overlapping and redundant signalling receptors. The identification of other cytoplasmic signalling molecules that are involved in DNA sensing is an important task. A better understanding of intracellular DNA recognition could lead to important targets for the development of therapies for DNA-related immune diseases.

Abstract

The recognition of nucleic acids is one strategy by which cells can detect infectious agents. As life is ultimately determined by the existence of nucleic acids, this defence strategy has evolved in many different organisms and operates effectively in many different cell types. Here, we review the recent progress in our understanding of the molecular mechanisms by which DNA activates cells to induce inflammation and antimicrobial immunity. DNA can be detected in different cellular compartments and can induce a range of cellular responses, such as an antiviral response and pyroptotic cell death together with the maturation and release of active interleukin-1β.

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Figure 1: Recognition of intracellular DNA triggers transcriptional activation of pro-inflammatory genes and proteolytic activation of caspases.
Figure 2: Activation of transcriptional innate immune responses by intracellular DNA.
Figure 3: Activation of a proteolytic innate immune response by intracellular DNA.

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Acknowledgements

This work was supported by grants to V.H. from the German Research Foundation (SFB704) and the European Research Council (ERC-2009-StG 243046) and to E.L. from the US National Institutes of Health (AI-065483 and AI-083713) and the Dana Foundation.

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Authors and Affiliations

  1. Institute for Clinical Chemistry and Pharmacology, University Hospital, University of Bonn,

    Veit Hornung

  2. Institute for Innate Immunity, University Hospital, University of Bonn, Sigmund-Freud-Strasse 25, Bonn, 53127, Germany

    Eicke Latz

  3. Division of Infectious Diseases & Immunology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, 01605, Massachusetts, USA

    Eicke Latz

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Glossary

Type I interferons

(IFNs). Type I IFNs bind to the IFNα receptor (IFNAR) cell surface complex, which consists of IFNAR1 and IFNAR2 chains. The type I IFNs in humans are mainly IFNα, IFNβ and IFNω and these IFNs mediate the inhibition of viral replication, activate natural killer cells and macrophages and increase antigen presentation to T cells during infections and during an immune response to tumour cells.

Retroelements

Retroelements (also known as retrotransposons) are transposable genetic elements that mediate their transposition life cycle through a process that involves the reverse transcription of RNA to DNA. Three main groups of retroelements exist in the human genome: long interspersed nuclear elements (LINEs; which are autonomous retrotransposons), small interspersed nuclear elements (SINEs) and long terminal repeat (LTR) retrotransposons. In the human genome, a few LINE retrotransposons (L1s) are active and can move their own and SINE sequences into different genomic locations. SINEs are nonautonomous retrotransposons that do not encode reverse transcriptase activity and therefore require LINEs for their propagation.

Systemic lupus erythematosus

(SLE). This is a prototypical nucleic acid-triggered autoimmune disease. High titres of autoantibodies specific for nucleoproteins, DNA and RNA can be found in the sera of patients with SLE and these autoantibodies induce immune-mediated tissue inflammation and damage.

RNA polymerase III

In eukaryotes, transcription is carried out by three distinct DNA-dependent RNA polymerases, known as RNA polymerase I, RNA polymerase II and RNA polymerase III. These RNA polymerases are multisubunit enzyme complexes that share a structurally conserved core, but they differ in the composition of subunits located at the outer part of the transcription complex. RNA polymerase III transcribes non-coding RNAs including, but not limited to, transfer RNAs, ribosomal 5S rRNA, small nuclear RNAs, small nucleolar RNAs, microRNAs and Piwi-interacting RNAs.

IFN regulatory factor

(IRF). A transcription factor involved in the regulation of IFN gene transcription. IRF3 and IRF7 have both been implicated downstream of the recognition pathways for intracellular DNA.

TANK-binding kinase 1

(TBK1). A serine/threonine kinase that phosphorylates and thereby activates IRF3 and IRF7, allowing their nuclear translocation. This leads to the production of type I IFNs.

Pyroptosis

A form of cell death that is triggered concomitantly with the activation of the inflammasome and requires caspase-1 activity. During pyroptotic cell death, one single large supramolecular complex consisting of ASC and eventually other inflammasome components forms to activate caspase-1.

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Hornung, V., Latz, E. Intracellular DNA recognition. Nat Rev Immunol 10, 123–130 (2010). https://doi.org/10.1038/nri2690

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