Intracellular DNA recognition

Abstract

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.