Role of the cGAS–STING pathway in systemic and organ-specific diseases

Abstract

Cells are equipped with numerous sensors that recognize nucleic acids, which probably evolved for defence against viruses. Once triggered, these sensors stimulate the production of type I interferons and other cytokines that activate immune cells and promote an antiviral state. The evolutionary conserved enzyme cyclic GMP–AMP synthase (cGAS) is one of the most recently identified DNA sensors. Upon ligand engagement, cGAS dimerizes and synthesizes the dinucleotide second messenger 2′,3′-cyclic GMP–AMP (cGAMP), which binds to the endoplasmic reticulum protein stimulator of interferon genes (STING) with high affinity, thereby unleashing an inflammatory response. cGAS-binding DNA is not restricted by sequence and must only be >45 nucleotides in length; therefore, cGAS can also be stimulated by self genomic or mitochondrial DNA. This broad specificity probably explains why the cGAS–STING pathway has been implicated in a number of autoinflammatory, autoimmune and neurodegenerative diseases; this pathway might also be activated during acute and chronic kidney injury. Therapeutic manipulation of the cGAS–STING pathway, using synthetic cyclic dinucleotides or inhibitors of cGAMP metabolism, promises to enhance immune responses in cancer or viral infections. By contrast, inhibitors of cGAS or STING might be useful in diseases in which this pro-inflammatory pathway is chronically activated.

Regulation of cGAS Activity and Downstream Signaling

“…cGAS activation also causes other diseases, including neurological and macular degeneration and liver and renal diseases. Several excellent reviews discussed these topics [ 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 ]. Therefore, we discussed these diseases briefly in the following section…”

“…Moreover, aging is a crucial factor in precipitating neurological disorders via augmenting cGAS-STING signaling and generation of aged diploid fibroblast cells [ 172 , 179 , 180 , 181 ]. In Alzheimer’s patients, oxidative stress induced by the accumulation of tau and beta-amyloid protein aggregates in the neurons leads to cell death and activation of cGAS-STING signaling [ 178 , 180 , 182 , 183 ].…”

“…Persistent cGAS-STING activation is also a leading cause of kidney injuries such as glomerulonephritis, vasculitis, and chronic kidney injury that can culminate in kidney fibrosis [ 176 , 188 ]. Cell death occurring from post-drug-induced nephrotoxicity, diabetic nephropathy, and ischemia-induced renal injury also activated cGAS-STING activation in the renal tubules [ 178 ]. Thus, initial insults in various tissues such as microglia, hepatocytes, and renal tubules can cause neurological, liver, and kidney diseases which can be aggravated further by aging.…”

Duck cGAS inhibits DNA and RNA virus replication by activating IFNs and antiviral ISGs

“…cGAMP binds to the stimulator of interferon genes (STING) localized at the endoplasmic reticulum (ER) membrane ( 10 ). Upon activation, STING, an important signaling component of the DNA sensing pathway that induces type-I IFN production, recruits TANK-binding kinase-1 (TBK1) to form a STING-TBK1 complex ( 9 , 11 ). The STING-TBK1 complex then translocates from the ER to the perinuclear lysosomal compartment through an autophagy-like process and subsequently activates the transcription factors IRF3 and NF- κB ( 9 , 10 , 12 ).…”

MLKL Deficiency Attenuated Hepatocyte Oxidative DNA Damage by Activating Mitophagy to Suppress Macrophage cGAS-STING Signaling During Liver Ischemia and Reperfusion Injury.

“…Moreover, cGAS, a major DNA sensor, produces the second messenger 2',3'-cyclic GMP-AMP to activate STING, leading to the production of type I interferons and other immune mediators. (6) In addition to bacterial and viral DNAs, host self-genomic or mitochondrial DNA can stimulate cGAS (31). Recent studies have shown that the cGAS-STING pathway plays an important role in various liver diseases.…”