Signaling by cGAS-STING in Neurodegeneration, Neuroinflammation, and Aging

Abstract

Recognition of foreign or misplaced nucleic acids is one of the principal modes by which the immune system detects pathogenic entities. When cytosolic DNA is sensed, a signal is relayed via the cGAS-STING pathway: this involves the activation of cyclic GMP-AMP (cGMP-AMP) synthase (cGAS) and generation of the cyclic dinucleotide cGAMP, followed by the induction of stimulator of interferon genes (STING). The cGAS-STING pathway responds to viral, bacterial, and self-DNA. Whereas it generally mediates immune surveillance and is often neuroprotective, excessive engagement of the system can be deleterious. This is relevant in aging and age-related neurological diseases, where neuroinflammation contributes to disease progression. This review focuses on cGAS-STING signaling in aging, neurodegeneration, and neuroinflammation, and on therapeutic implications.

Keywords: Huntington’s disease; ataxia telangiectasia; cyclic GAMP; innate immune system; interferon-stimulated genes; senescence.

Figure 1.. The cGAS-STING signaling pathway.

The cyclic GAMP synthase (cGAS) binds cytosolic DNA derived from the nucleus, mitochondria and pathogens such as viruses and bacteria to produce cGAMP from ATP and GTP. Cells also harbor DNases such as TREX1 and others which eliminate cytosolic DNAs to prevent activation of cGAS-STING as part of a homeostatic mechanism. cGAMP initiates the signaling cascade by binding to the endoplasmic reticulum (ER)-resident adaptor protein STING, which translocates to the ER-Golgi intermediate compartment (ERGIC) and to the Golgi apparatus, where it binds the TANK binding kinase (TBK1), which phosphorylates the interferon regulatory factor 3 (IRF3). IRF3 translocates to the nucleus and transcribes interferon stimulated genes (ISGs). TBK1 also activates inhibitor of nuclear factor β kinase (IKK), which in turn phosphorylates IκBα, which relieves inhibition of NF-κB (comprising the p65 and p50 subunits). NF-κB moves into the nucleus and transcribes its target genes. Together, the cytokines and interferons produced mount an immune response against the pathogenic entity.

Figure 2.. Type I interferon signaling and downstream effects in neurodegeneration.

A) Signaling cascade mediated by Type I interferons (IFN-I). IFN-I acts through IFNAR, comprising IFNAR1 and IFNAR2 subunits, associated with the tyrosine kinase 2 (Tyk2) and JAK1, respectively [20]. Activation of Tyk2 and JAK1 activates the STAT1 and STAT2 proteins which bind to the IRF9 forming heterotrimeric transcription factor complex termed IFN‐stimulated gene factor‐3 (ISGF3). ISGF3 binds genes harboring the Interferon-sensitive response element (ISRE) to stimulate the transcription of interferon stimulated genes (ISGs), which include proinflammatory cytokines such as IL-1β, IL-6, TNF-α. B) Schematic representation of the events contributing to neurodegeneration by excessive IFN-I signaling. Danger signals or invading pathogens activate microglia to release proinflammatory cytokines, which act on astrocytes, which in turn are activated to release proinflammatory cytokines. The activated astrocytes and microglia cooperate and generate proinflammatory cytokines as well as reactive oxygen species (ROS) and reactive nitrogen species (RNS). RNS is generated by induction of inducible nitric oxide synthase (iNOS), which produces nitric oxide (NO). NO and its highly reactive product peroxynitrite (ONOO), which can damage neurons. Neurotoxicity may also be induced by activation of N-methyl D-aspartate (NMDA) receptors. In addition, activation of the p53 and p65 pathways may induce apoptosis.

Figure 3.. Microglia induce STING dependent antiviral programs in neurons and prime the TLR3 pathway in astrocytes.

Microglia, the resident macrophages in the brain, are the predominant cell type which activate the cGAS-STING signaling cascade. Microglia secrete interferons, which act on the interferon A receptors on neurons (IFNAR) and elicit antiviral defense mechanisms in the neurons. In parallel, the astrocytes are primed as well, to alleviate inflammation. Excessive engagement of this system can cause chronic neuroinflammation.

Figure 4.. Aging and the cGAS-STING pathway.

When cells are stressed by various stimuli, which lead to escape of nuclear or mitochondrial DNA to the cytosol, the cGAS STING pathway is activated, followed by degradation of STING by autophagy. Normal cells also harbor DNAses that degrade cytosolic DNA. During aging, the expression of these DNAses decrease, leading to a build-up of extranuclear DNA. Moreover, compromised autophagy delays clearance of activated STING and other cell debris, leading to further accumulation of cytosolic DNA, further amplifying the cycle and leading to heightened inflammation.