The interferon response to intracellular DNA: why so many receptors?

Abstract

The detection of intracellular DNA has emerged to be a key event in the innate immune response to viruses and intracellular bacteria, and during conditions of sterile inflammation and autoimmunity. One of the consequences of the detection of DNA as a 'stranger' and a 'danger' signal is the production of type I interferons and pro-inflammatory cytokines. Much work has been dedicated to the elucidation of the signalling cascades that activate this DNA-induced gene expression programme. However, while many proteins have been proposed to act as sensors for intracellular DNA in recent years, none has been met with universal acceptance, and a theory linking all the recent observations is, as yet, lacking. This review presents the evidence for the various interferon-inducing DNA receptors proposed to date, and examines the hypotheses that might explain why so many different receptors appear to be involved in the innate immune recognition of intracellular DNA.

Keywords: AIM2; ASC; ATLD; ATM; Ataxia telangiectasia mutated; BMDC; BMDM; CARD; CT; DAI; DNA receptor; DNA virus; DNA-PKcs; DNA-dependent activator of IRFs; DNA-dependent protein kinase catalytic subunit; EBER; EBV; Epstein–Barr virus; Epstein–Barr virus encoded small RNA; HFF; HMGB; HSV; HT; IFI16; IFN; IFNγ-inducibe protein 16; IL; IRF3; ISD; Innate immunity; Interferon; MAPK; MAVS; MDA5; MDDC; MDM; MEF; MVA; Meiotic recombination 11; Modified Vaccinia Ankara; Mre11; NF-kB; PAMP; PBMC; PM; PRR; RIG-I; RIG-like receptor; RLR; RNA interference; RNAi; SLE; STING; SeV; Sendai virus; TANK-binding kinase; TBK1; TLR; TREX1; Toll-like receptor; VACV; VSV; Z-DNA binding protein; ZBP1; absent in melanoma 2; apoptosis-associated speck-like protein containing a CARD; ataxia-telangiectasia-like disorder cells; bone marrow-derived dendritic cells; bone marrow-derived macrophages; cGAMP; cGAS; calf thymus; caspase activation and recruitment domain; cyclic GMP-AMP; cyclic GMP-AMP synthase; double-stranded; ds; herpes simplex virus; herring testis; high mobility group box; human foreskin fibroblasts; immunostimulatory DNA; interferon; interferon regulatory factor; interleukin; melanoma differentiation factor 5; mitochondrial antiviral signalling; mitogen-activated protein kinase; monocyte-derived dendritic cells; monocyte-derived macrophages; mouse embryonic fibroblasts; nuclear factor kB; pathogen-associated molecular pattern; pattern recognition receptor; peripheral blood monocytic cells; peritoneal macrophages; retinoic acid-inducible gene; single-stranded; small nuclear RNA; snRNA; ss; stimulator of IFN genes; systemic lupus erythematosus; tRNA; three prime repair exonuclease 1; transfer RNA; vaccinia virus; vesicular stomatitis virus.