Cytosolic DNA sensors regulating type I interferon induction

doi:10.1016/j.it.2011.08.004

Trends in Immunology

Volume 32, Issue 12, December 2011, Pages 574-581

https://doi.org/10.1016/j.it.2011.08.004 Get rights and content

Type I interferon (IFN) induction is a crucial anti-pathogen response mediated by innate immune stimulation. Although it has been appreciated for some time that the presence of pathogen DNA within a cell leads to a type I IFN response, it is only in the past few years that some of the key signalling proteins and DNA sensors that regulate this response have been uncovered. Here, we review the nature of these DNA sensors, which include a new family of pattern recognition receptors termed the AIM2-like receptors, and consider the implications of their discovery for understanding emerging principles of innate immune DNA sensing. Furthermore, we discuss how their discovery provides a rationale as to why accumulation of self-DNA mediates IFN-dependent autoimmunity.

Section snippets

Type I interferon (IFN) response to DNA

The innate immune system responds to the presence of pathogens or danger by recognising pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) respectively, leading to altered gene expression, immune effector mechanisms and ultimately a return to homeostasis. PAMPs and DAMPs are detected by several classes of host pattern recognition receptors (PRRs) including the Toll-like receptors (TLRs), RIG-like receptors (RLRs), NOD-like receptors (NLRs) and C-type

Signalling components involved in the cytosolic DNA response

Although the specific receptor molecules involved in triggering TLR9-independent DNA sensing pathways were unknown until recently, studies examining the cellular responses induced by transfecting different types of DNA molecules into cells, or infecting cells with DNA viruses, have uncovered several signalling proteins functioning downstream of DNA sensors that are required for cytosolic DNA responses (Figure 1). Apart from the transcription factors nuclear factor (NF)-κB and IFN regulatory

Novel intracellular DNA sensors for IFN induction

Neither TBK1 nor STING directly recognises DNA in the cytosol. Rather, upstream cytosolic DNA sensors have recently been described, which are proposed to have the capacity to bind directly to DNA, and engage signalling pathways converging on NF-κB and IRF activation, leading to type I IFN induction (Figure 1). These sensors display some selectivity in terms of cell type, the pathogens sensed, and the exact nature of the DNA ligand tested (Table 1). However, work to date suggests that it is

Negative regulation of intracellular DNA sensing pathways

The inappropriate induction of type I IFNs leads to the onset of such autoimmune disorders as SLE and Aicardi–Goutieres syndrome (AGS). The detrimental effects of dysregulated type I IFN production is underscored by the fatal encephalopathy induced by overproduction of IFN-α in AGS [43]. Furthermore, irf3 or ifnαβR deletion can reverse the lethal phenotype of autoimmune disorders in mice 44, 45, 46. Accordingly, inappropriately generated self nucleic acid must be cleared efficiently to prevent

Viral evasion of innate DNA sensing mechanisms

Most PRRs identified to date are subject to targeting by viral evasion mechanisms [66], and this is also becoming apparent for some of the novel cytosolic DNA sensors (Table 2). Before the discovery of DNA sensors, it was already appreciated that multiple viral mechanisms exists to antagonise TBK1 signalling (reviewed in [66]), however, it has also now been shown that some viruses also target the novel DNA sensors more directly. For example, murine CMV encodes a receptor-interacting protein

DNA sensing: future perspectives and outstanding questions

Understanding of innate intracellular DNA sensing pathways has advanced rapidly in recent years. As described above, a number of candidate sensors of intracellular DNA have now been described. However, key questions remain to be addressed. Whether all of the current described DNA sensors are actually true receptors requires clarification. For example, specific regulation of IFN-β by LRRFIP1 independently of any role in TNF-α induction coupled with no role in IRF3 or p65 activation points to a

Acknowledgements

The authors are supported by Science Foundation Ireland.

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Trends in Immunology

ReviewCytosolic DNA sensors regulating type I interferon induction

Section snippets

Type I interferon (IFN) response to DNA

Signalling components involved in the cytosolic DNA response

Novel intracellular DNA sensors for IFN induction

Negative regulation of intracellular DNA sensing pathways

Viral evasion of innate DNA sensing mechanisms

DNA sensing: future perspectives and outstanding questions

Acknowledgements

Immunity

Immunity

Cell Host Microbe

Blood Cells Mol. Dis.

Cell

J. Autoimmun.

Am. J. Pathol.

Immunity

Exp. Cell Res.

A Toll-like receptor recognizes bacterial DNA

Nature

Toll-like receptor-independent gene induction program activated by mammalian DNA escaped from apoptotic DNA degradation

J. Exp. Med.

Toll-like receptor 9-dependent and -independent dendritic cell activation by chromatin-immunoglobulin G complexes

J. Exp. Med.

Nucleosome, the main autoantigen in systemic lupus erythematosus, induces direct dendritic cell activation via a MyD88-independent pathway: consequences on inflammation

J. Immunol.

Macrophage activation by a DNA/cationic liposome complex requires endosomal acidification and TLR9-dependent and -independent pathways

J. Leukoc. Biol.

Endosomal translocation of vertebrate DNA activates dendritic cells via TLR9-dependent and -independent pathways

J. Immunol.

Induction of type I interferons by bacteria

Cell Microbiol.

A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA

Nat. Immunol.

TANK-binding kinase-1 plays an important role during in vitro and in vivo type I IFN responses to DNA virus infections

J. Immunol.

TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines

Nature

STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling

Nature

MPYS, a novel membrane tetraspanner, is associated with major histocompatibility complex class II and mediates transduction of apoptotic signals

Mol. Cell. Biol.

ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization

Proc. Natl. Acad. Sci. U.S.A.

STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity

Nature

Absent in melanoma 2 is required for innate immune recognition of Francisella tularensis

Proc. Natl. Acad. Sci. U.S.A.

The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1

Nat. Immunol.

The N-ethyl-N-nitrosourea-induced Goldenticket mouse mutant reveals an essential function of Sting in the in vivo interferon response to Listeria monocytogenes and cyclic dinucleotides

Infect. Immun.

Identification and characterization of a loss-of-function human MPYS variant

Genes Immun.

DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response

Nature

Human cytomegalovirus induces the interferon response via the DNA sensor ZBP1

J. Virol.

Regulation of innate immune responses by DAI (DLM-1/ZBP1) and other DNA-sensing molecules

Proc. Natl. Acad. Sci. U.S.A.

Receptor-interacting protein homotypic interaction motif-dependent control of NF-kappa B activation via the DNA-dependent activator of IFN regulatory factors

J. Immunol.

DAI/ZBP1 recruits RIP1 and RIP3 through RIP homotypic interaction motifs to activate NF-kappaB

EMBO Rep.

RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate

Nat. Immunol.

RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway

Cell

Double-stranded DNA and double-stranded RNA induce a common antiviral signaling pathway in human cells

Proc. Natl. Acad. Sci. U.S.A.

Review
Cytosolic DNA sensors regulating type I interferon induction