STING: infection, inflammation and cancer

Abstract

The rapid detection of microbial agents is essential for the effective initiation of host defence mechanisms against infection. Understanding how cells detect cytosolic DNA to trigger innate immune gene transcription has important implications - not only for comprehending the immune response to pathogens but also for elucidating the causes of autoinflammatory disease involving the sensing of self-DNA and the generation of effective antitumour adaptive immunity. The discovery of the STING (stimulator of interferon genes)-controlled innate immune pathway, which mediates cytosolic DNA-induced signalling events, has recently provided important insights into these processes, opening the way for the development of novel immunization regimes, as well as therapies to treat autoinflammatory disease and cancer.

Figure 1. STING-dependent innate immune signalling.

Stimulator of interferon genes (STING) is activated by cyclic dinucleotides (CDNs) produced by certain bacteria or by cyclic GMP–AMP synthase (cGAS), which in the presence of ATP and GTP catalyses the production of a type of CDN referred to as cGAMP (cyclic GMP–AMP) following binding to cytosolic DNA species (from viruses or bacteria, or self -DNA from the nucleus or mitochondria). STING is associated with the endoplasmic reticulum (ER) and, following binding to CDNs, STING forms a complex with TANK-binding kinase 1 (TBK1). This complex traffics to the perinuclear Golgi via pre-autophagosomal-like structures — a process resembling autophagy — to deliver TBK1 to endolysosomal compartments where it phosphorylates the transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor-κB (NF-κB). Stimulation of the IRF3 and NF-κB signalling pathways leads to the induction of cytokines and proteins, such as the type I interferons (IFNs), that exert anti-pathogen activity. c-di-AMP, cyclic di-AMP; dsDNA, double-stranded DNA; ISGF3, interferon-stimulated gene factor 3; JAK, Janus kinase; STAT, signal transducer and activator of transcription; TYK, tyrosine kinase. PowerPoint slide

Figure 2. STING signalling is essential for anti-pathogen host defence.

DNA viruses and cyclic dinucleotides (CDNs) produced by certain bacteria stimulate stimulator of interferon genes (STING) activity to trigger the production of primary innate immune genes. The products from these genes can exert direct intracellular anti-pathogen activity as well as trigger the production of type I interferons (IFNs) and other cytokines that can protect uninfected cells and stimulate adaptive immune responses. cGAS, cyclic GMP–AMP synthase. PowerPoint slide

Figure 3. STING in autoinflammatory disease.

Cyclic GMP–AMP synthase (cGAS) binds to cytosolic self-DNA and generates stimulator of interferon genes (STING)-activating cyclic dinucleotides (CDNs). The activation of STING by self-DNA can induce autoinflammatory disease. Mutations in three-prime repair exonuclease 1 (Trex1), which encodes a DNA exonuclease that degrades single-stranded DNA and double-stranded DNA substrates, can cause STING activation through failure to eliminate self-DNA that has leaked into the cytosol of the cell. Conversely, mutations in STING itself can lead to constitutive activity and autoinflammtory diseases such as STING-associated vasculopathy with onset in infancy. PowerPoint slide

Figure 4. STING control of tumour development.

a | Stimulator of interferon genes (STING)-driven inflammation-associated cancer. Carcinogens such as 7,12-dimethylbenz[α]anthracene (DMBA) cause DNA damage, which can result in the leakage of DNA into the cytosol and the intrinsic chronic activation of the STING pathway. This event attracts phagocytes that engulf damaged cells. The self-DNA from engulfed cells can extrinsically activate STING in the phagocytes, which results in the production of more cytokines and growth factors that can activate tumour growth-promoting pathways as well as attract more immune cells to the region. b | STING and wound repair function. Carcinogens and inflammatory agents such as azoxymethane (AOM) and dextran sulfate sodium (DSS) also cause DNA damage that can result in the leakage of DNA into the cytosol and cause activation of the intrinsic STING pathway in intestinal cells. This event produces cytokines such as interleukin-1β (IL-1β) or IL-18 that enable wound repair to commence. Loss of STING prevents wound repair from occurring and may enable the infiltration and growth of genotoxic bacteria that trigger STING-independent inflammation and perhaps cancer (not shown). c | STING-dependent antitumour cytotoxic T lymphocyte (CTL) priming. Dying tumour cells are engulfed by antigen-presenting cells such as CD8α⁺ dendritic cells (DCs). DNA from the engulfed cell triggers STING-dependent cytokine production in the phagocyte, which facilitates cross-presentation and antitumour CTL responses. Agonists of STING have been shown to exert potent antitumour activity. CDN, cyclic dinucleotide; cGAS, cyclic GMP–AMP synthase; IFN, interferon; TCR, T cell receptor. PowerPoint slide