Regulation of cGAS Activity and Downstream Signaling: History
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Contributor:
Bhagwati Joshi
,
Jagdish Chandra Joshi
,
Dolly Mehta

Cyclic GMP-AMP synthase (cGAS) is a predominant and ubiquitously expressed cytosolic dsDNA sensor that activates innate immune responses by producing a second messenger, cyclic GMP-AMP (cGAMP), and activating the stimulator of interferon genes (STING). cGAS contains a highly disordered N-terminus, which can sense genomic/chromatin DNA, while the C terminal of cGAS binds dsDNA liberated from various sources, including mitochondria, pathogens, and dead cells. Furthermore, cGAS cellular localization dictates its response to foreign versus self-DNA.

  • cGAS
  • STING
  • calcium
  • autoimmunity

1. Introduction

Pathogenic invaders, including bacteria and viruses, and genetic mutations associated with immunogenic diseases continuously challenge host cell homeostasis [1].A defining feature of innate immunity by the infected cell is to liberate DNA/RNA to induce the cell death pathway through the pattern recognition receptors (PRR) [2][3]. Sun et al. initially identified cyclic GMP–AMP synthase (cGAS) as one of the most crucial cytosolic DNA sensors [4]. Since then, the knowledge of how the liberated DNA/RNA in the host cell provokes an immune response, particularly for the cGAS and its effector, stimulator of interferon genes (STING), has burgeoned. cGAS is now one of the most intensely studied areas of basic and clinical research leading to publications of several excellent research [5][6]. As cGAS is one of the most rapidly diverging genes in the mammalian genome [7][8], more understanding of cGAS function and downstream signaling is required.

2. Regulation of cGAS Activity

2.1. Transcriptional Regulation of cGAS

The transcriptional regulation of cGAS activation is not a well-explored area. cGAS promoter contains three IFN-sensitive response elements (ISREs) and one STAT1 binding site that can potentially induce cGAS synthesis by type 1-IFN [9]. As h-cGAS and m-cGAS are <60% homologous, cGAS can be synthesized differentially in different species. Chen et al., characterized the molecular mechanisms controlling the cGAS transcriptional activity [10]. By a series of 5′ deletion and promoter constructions, they found that the region (−414 to +76 relatives to the transcription start site) was sufficient for promoter activity [11]. Mutation of SP1 and CREB binding sites in this promoter region led to an apparent reduction of the cGAS promoter activity [11]. Moreover, elevated expression of microRNA (miR)-93/25 observed in breast cancer facilitates tumor evasion from immune surveillance and destruction partially through downregulating cGAS expression. Thus, miR, SP1 and CREB may control cGAS synthesis and inflammatory signaling.

2.2. Translational Regulations of cGAS Activation

Posttranslational modifications such as phosphorylation, ubiquitination, sumoylation, and acetylation play a pivotal role in cGAS signaling regulation, dimerization, and transcriptional regulation, ultimately regulating a plethora of biological processes such as cell survival and DNA damage (DDR) in response to genomic insult.

2.2.1. Phosphorylation

cGAS contains many serine/threonine residues within its catalytic sites and C-terminus [12]. Phosphorylation of cGAS by serine kinases such as serine/threonine-protein kinase (AKT), cyclin-dependent kinase-1 (CDK1), and Aurora kinase B (AKB) has been shown to repress cGAS activity and thereby immune response [13][14][15]. Seo et al. showed that HSV-1 infection on 293T cells leads to AKT activation which in turn phosphorylated cGAS at S291 (m-cGAS) and S305 (h-cGAS) [14]. cGAS phosphorylation at S291/S301 impaired cGAS generation of cGAMP and thereby the production of type 1 IFN [14]. In another study, HSV-1 infection of human primary fibroblasts and HEK293T cells caused cGAS phosphorylation at multiple serine sites (Ser37, Ser116, Ser201, Ser221, Ser263) which also suppressed cGAS activity during their post-translational modification, however, the signaling behind the phosphorylation is not yet clearly understood [12]. Zhong et al., showed similar suppression of cGAS activity after phosphorylation at S305 residue by CDK1-cyclin B kinase complex in mitotic cells [15]. Li et al., recently demonstrated that hyperphosphorylation of cGAS N-terminus at serine and threonine residues (Ser13, Ser37, Ser64, Thr69, Thr91, Ser116, Ser129, and Ser143) by AKB blocked chromatin DNA sensing in mitotic cells [13]. Thus, it is plausible that AKT, CDK1, and AKB govern cGAS phosphorylation to control cGAS activation during critical phases of the cell cycle like DNA replication (S) and mitotic division (M). However, cGAS phosphorylation by these kinases was reversed either by protein phosphatase 1 (PP1) [15] or PP6 [16] reinstating cGAS DNA-sensing ability.
Interestingly, cGAS also contains several tyrosine residues of unknown functions. A study showed that the phosphorylation of Tyr215 in hcGAS by BLK (B lymphocyte kinase) retained cGAS in the cytoplasm for cytosolic DNA sensing [17]. Intriguingly, researchers showed that synthetic dsDNA as well DNA isolated from Pseudomonas aeruginous and HSV-1 infection of vascular cells induced cGAS phosphorylation at Y215 and Y242 residues by the tyrosine kinase, cSRC (data not published). researchers further showed that cGAS phosphorylation at Y215/Y242 promoted cGAS-DNA liquid phase condensation and cGAS activation since transduction of mutated cGAS in endothelial cells inhibited these events (unpublished). Thus, serine and tyrosine phosphorylation of cGAS seems to have an antagonistic role in regulating cGAS activity.

2.2.2. Ubiquitination

Several ubiquitin ligases are shown to regulate cGAS activity. The E3 ligase, TRIM56, monoubiquitinated cGAS at Lys335 which resulted in a marked increase in its dimerization, DNA-binding activity, and cGAMP production [18]. TRIM41 also promoted cGAS monoubiquitination using biochemical assays [19]. Wang et al., reported that ER ubiquitin ligase, RNF185, specifically catalyzed the K27-linked poly-ubiquitination of cGAS at K-384 and promoted its enzymatic activity [20]. The patients suffering from Systemic Lupus Erythematosus (SLE), has constitutive activation of cGAMP-STING signaling [21], and displayed elevated expression of RNF185 mRNA [20]. Whether increased RNF185 mRNA was the factor in increasing cGAS-STING signaling is unclear. It was reported that upon DNA virus infection, USP14 was recruited by TRIM14 to remove K48-linked ubiquitin chains at the Lys414 site in h-cGAS, leading to cGAS stabilization to promote antiviral innate immunity [22]. Similarly, USP27X [23][24] and USP29 [25] have also been reported to stabilize cGAS proteins by cleaving K48-linked poly-ubiquitin chains from cGAS, and both serve as positive regulators in activating innate immunity to fight against DNA viral infection. Thus, deubiquitinase and ubiquitinase have additional control on cGAS activation.

2.2.3. SUMOylation

Like ubiquitination, TRIM38 maintains SUMOylation of m-cGAS at Lys217 and Lys464 residues (corresponding to Lys231 and Lys479 in hcGAS), which prevented K48-linked cGAS polyubiquitination and degradation [24]. On the other hand, SENP7 alleviates SUMO-mediated suppression of cytosolic DNA sensing by removing cGAS SUMOylation [26].

2.2.4. Acetylation

The acetylation of cGAS can regulate cGAS activity either positively or negatively depending upon the acetylation sites. The protein acetylation occurs on lysine residues by the action of acetyl-transferases and deacetylases [27]. Dai et al., found acetylation of hcGAS at Lys384, Lys394, and Lys414 residues at resting state which restrained cGAS activity [28]. However, deacetylation of these sites upon DNA challenge enabled cGAS activation [28]. Thus, this group introduced a promising role of aspirin, which could directly acetylate cGAS to inhibit cGAS activation, as a therapeutic strategy in treating autoimmune diseases, such as Aicardi–Goutieres syndrome (AGS) [12][28][29]. Recently, the N-terminal domain of human cGAS was reported to be acetylated by lysine acetyltransferase, KAT5, at Lys47/Lys56/Lys62/Lys83 residues. These acetylation events increased cGAS binding with DNA and activity in response to DNA challenge [29]. Further functional validation suggests that acetylation at Lys414 suppresses, while acetylation at Lys198 promotes h-cGAS activation. Interestingly, h-cGAS-Lys198 acetylation was found to be decreased by quantitative proteomics upon infection by either HSV-1 or HCMV (human cytomegalovirus), suggesting that these DNA viruses might evade innate-immune surveillance by hijacking acetylation of cGAS at these sites [12].
Thus, phosphorylation, ubiquitination, SUMOylation, and acetylation all control cGAS activity. How these posttranslational modifications of cGAS are regulated at different stages of infection and whether ubiquitination precede acetylation or vice versa may provide an approach to specifically target cGAS activity while preserving host-defense.

3. cGAS Activation of STING

cGAS-induced cGAMP binds STING (stimulator of interferon genes) in the ER (endoplasmic reticulum) membrane to induce inflammatory signaling [14][30]. STING is a transmembrane homodimer that upon being activated phosphorylates itself and translocates to the Golgi apparatus where it binds to and activates TANK-binding kinase 1 (TBK1) and IFN regulatory factor 3 (IRF3) via a phosphorylation-dependent mechanism, leading to the generation of type 1 IFN [22][31].

3.1. Role of Gasdermin D

Gasdermin D (GSDMD) forms ~21 nm diameter oligomeric pores in the plasma membrane which induces cell death (pyroptosis) [32]. Studies showed that caspases (caspase-1 and -4/-5/-11) cleaved human and mouse GSDMD after Asp275 and Asp276 respectively, generating an N-terminal cleavage product (GSDMD-N) [33]. GSMD-N triggered pyroptosis and the release of inflammatory cytokines IL-1β and IL-18 and downstream signaling [34]. Interestingly, Huang et al., showed that GSDMD-N could form pores in the mitochondria to release mitochondrial DNA (mtDNA) that activates the cGAS-STING pathway to suppress cellular proliferation [35]. A recent study also showed that PIP2 content in the membrane retains GSDMD pores predominantly in the open state [36]. Since PIP2 induces cGAS translocation [37] it is possible that membrane PIP2 levels control both GSDMD and cGAS activation and thereby STING signaling. Thus, GSDMD and cGAS may operate in parallel to trigger STING signaling [38].

3.2. Role of Ca2+ Signaling

ER also forms the hub for regulating a rise in intracellular Ca2+ signaling. An increase in cytosolic Ca2+ is required for several primary cellular processes including apoptosis, proliferation, cellular motility, differentiation and exocytosis, and innate immunity [39][40][41]. Interestingly, Ca2+ signaling seems to have a dual role in regulating cGAS-STING signaling since STIM1 (stromal interaction molecule 1), an established sensor of Ca2+ in ER physically interacts with STING via its EF-hand domain and inhibits STING activity by both cGAMP and cGAMP independent STING activation [42]. Similarly, in systemic lupus erythematosus (SLE) hyperactivation of cGAS-STING signaling in T cells also required suppression of Ca2+ homeostasis, but whether STIM1 was involved is not clear [43]. In contrast, the DNA-dependent activator of IFN-regulatory factors (DAI), which functions as a secondary cytoplasmic DNA sensor to cGAS, induces NF-κB and IRF3 in a calcium-dependent manner [44][45]. Likewise, the quenching of cytosolic Ca2+ by BAPTA-AM (a Ca2+ chelator) or CGP37157 (which inhibits the mitochondrial sodium-Ca2+ pump) dampened DAI-induced autoimmune response in macrophages [38].
STIM1 is a single-pass transmembrane protein and binds Ca2+ in the lumen of ER in several cell types such as T cells and endothelial cells. STIM1 organizes as puncta following ER-depletion and binds to plasmalemmal Ca2+ channels such as ORAI1 and TRPC1/TRPC4 at ER-PM junctions to mediate the influx of Ca2+ from the extracellular space into the cell by a process referred to as store-operated Ca2+ entry (SOCE) [46][47][48]. STIM1 inhibits STING in macrophages by anchoring it to the ER, which inhibits its translocation to the Golgi and thus halts STING-mediated IFN-β production. However, researchers showed that in alveolar macrophages, the most sentinel cells in the tissue, STIM1 is dispensable since endotoxin stimulated Ca2+ influx in a STIM independent but in transient receptor vanilloid potential (TRPV4) channel-dependent manner [49].
Ca2+ is known to activate calcium/calmodulin-dependent protein kinase II (CAMKII), which may alter cGAS activation of STING. CAMKII can bypass cGAS activity by activating STING via inducing the activity of AMP-activated protein kinase (AMPK) [50]. AMPK has been shown to induce STING signaling through repressing ULK1 [51][52]. ULK1 phosphorylates and negatively regulates cGAS-STING signaling [52]. However, ionomycin-induced saturating levels of cytosolic Ca2+ inhibited STING activity indicating that an optimal Ca2+ influx may be required for STING function [53]. PIP2 can suppress cGAS activity through AKT phosphorylation of cGAS [14]. Thus, there is a need to tease out whether Ca2+ influx promotes or dampens cGAS activity.
In mouse embryonic fibroblasts and human Jurkat T cells, loss of STING leads to elevated Ca2+ influx [54]. While in the absence of STING, STIM1 became enriched at ER-PM sites and this likely led to the dysregulated induction of store-operated Ca2+ entry. Thus, it is possible that the STIM1-STING binding under resting conditions reciprocally regulates the pool of STIM1 protein to maintain Ca2+ homeostasis. These findings also suggest that during STING activation, STIM1 may be free to translocate and interact with cGAS or ORAI1, resulting in a transient cytosolic Ca2+ influx. Future work studying this relationship will be important in enhancing the understanding of the interconnecting pathways linking innate immune signaling and Ca2+ homeostasis. However, the activation of cGAS-STING signaling during calcium influx and calcium-related signaling is yet to be explored.

4. cGAS-STING Pathway and Pathologies

4.1. Acute Lung Injury (ALI) and COVID-19

ALI is a devastating inflammatory condition of the lungs that is characterized by disruption of alveolar-capillary junctions leading to an uncontrolled influx of proteins rich fluid and blood cells into the alveolar space [55][56][57][58]. Neutrophils and tissue-resident macrophages propagate inflammatory responses by releasing various inflammatory cytokines and chemoattractants. However, these cells also seem to have a resolving role in ALI [59]. Upon sensing pathogens macrophages orchestrate the inflammatory signaling by releasing inflammatory cytokines leading to the influx of activated neutrophils [60]. Later these macrophages clean up the debris by a process called efferocytosis to resolve the lung inflammation [61][62]. Thus, based on their activation lung macrophages can acquire inflammatory (M1) or anti-inflammatory (M2) lineage [63][64]. The alveolar macrophages (AM), the major immune cells in the lungs, are the first offender of invading pathogens. Another subset of macrophages in the lungs are interstitial (IM) and monocytes-derived macrophages (MoMacs). While the role of IM remains unclear, MoMacs compensate for the dying AM and serve as an anti-inflammatory and pro-resolving macrophage.
IFN-β is one of the important cytokines in macrophages induced by viruses as well as bacteria [65][66]. IFN-β can be generated either by non-canonical (inducible signaling pathway) or canonical (signaling which is constitutively active) pathway and seem to dictate the outcome of ALI and patient mortality from COVID-19 as well as autoimmune diseases such as Aicardi-Goutieres syndrome (AGS), Systemic lupus erythematosus (SLE), and STING-associated vasculopathy with onset in infancy (SAVI), etc [67][68][69][70][71][72]. The initial induction of type I IFNs limits virus propagation, however, a sustained increase in IFN-β level in the later stage of the infection is associated with aberrant inflammation. Studies showed that type I &type III IFNs significantly precipitated the SARS-CoV-2 replication and pathological responses associated with SARS-CoV-2 and a crucial component of a skin lesion in these patients [73][74][75][76].
Researchers showed that conditional ablation of MoMacs during injury augmented the activation of cGAS-STING signaling by LPS and Pseudomonas aeruginous (PA) [56]. In WT mice LPS and PA resulted in reversible generation IFNβ leading to resolution of ALI. However, ablation of MoMacs during injury increased the production of secondary messenger, cGAMP in the lungs leading to persistent STING signaling and lung injury [56]. While the detailed mechanism remains to be parsed out, these researchers showed that MoMacs inhibit cGAS-STING signaling by generating a lipid mediator, sphingosine 1 phosphate. Consistently, the adoptive transfer of MoMacs in mice lacking endogenous MoMacs reduced IFN-β generation and resolved ALI.
In another study, Hong et al. showed that accumulated mtDNA can stimulate cGAS in endothelial cells leading to the expression of type I IFNs and cell death [35]. They showed that LPS activated gasdermin D, which formed mitochondrial pores to enhance the influx of mtDNA into the cytosol of endothelial cells [35]. mtDNA was recognized by the DNA sensor cGAS leading to the generation of the second messenger cGAMP, which suppressed endothelial cell proliferation by downregulating the signaling induced by the transcription factor, YAP1. Studies have also shown that in idiopathic pulmonary fibrosis patients (mt DNA) can be accumulated in type II alveolar epithelial cells due to ER stress and PINK 1 deficiency [77][78][79][80]. In COPD patients increased level of cell-free DNA in the buccal cell was associated with apoptotic or necrotic cell death [80][81]. It is possible therefore that mtDNA accumulation in Type II cells can exacerbate lung damage as these cells generate Type I epithelial cells to repair lung injury.
Using a lung-on-chip model, Domizio et al., showed that upon infection with SARS-CoV-2, macrophages released mitochondrial DNA which activated cGAS–STING signaling in endothelial cells leading to their death and irreversible IFN-β production [74]. Pharmacological inhibition of STING reduced severe lung inflammation induced by SARS-CoV-2 and improved disease outcome. In terms of preventive measures during viral infection, early induction of IFN-β before the high viral load was found to be protective, whereas late induction resulted in increased inflammation and lethal pneumonia [82][83].
Thus, these findings raise the possibility that cGAS-STING signaling in lung cells can exacerbate ALI, and therefore cell therapy (CD11b+-Mɸ) or STING inhibitors are valuable targets for the treatment of ALI pathology in inflammatory conditions

4.2. Adaptive Immunity

Immune system checks on the invading microbes by activating innate or adoptive immunity. As the name suggests innate immunity is antigen and memory-independent, the non-specific first line of defense dependent on pattern recognition receptors (PRRs) (discussed above). In contrast, adaptive immunity is antigen-dependent, specific for the pathogenic antigens, and has immunological memory to kill the pathogens if attacked by the same pathogens. Macrophages and T lymphocytes are the most representative cells of innate immunity and adaptive immunity, respectively. Macrophages, as major professional antigen-presenting cells (APCs), are best known for their ability to prime the host defense by engulfing foreign pathogens [84]. The DNA released through pathogens or endogenous necrotic/apoptotic cells activates the cGAS-STING signal pathway in macrophages, leading to the release of cytokines including IFN-β, which leads to the ani-viral response, to cope with various stresses and maintain homeostasis [85]. Over activation of the cGAS-STING signaling in macrophages can thereby lead to auto-immune diseases [31][86]. For instance, STING-associated vasculopathy in infancy (SAVI), Systemic Lupus Erythematosus (SLE), and Aicardi-Goutières syndrome (AGS) are auto-immune diseases caused by the overproduction of type-I interferon. In SAVI, mutation of STING (R281Q) in patients results in the gain of function of STING causing long-lasting IFN-β production and severe autoinflammatory diseases [87]. AGS is characterized by inherited encephalopathy and leads to severe mental and physical problems, that affect newborn infants. AGS occurs due to a genetic mutation in DNase II, Trex1 (also known as DNase III), or RNaseH2 [88][89][90]. However, in AGS, the mutation in DNAses leads to the amassing of cytosolic DNA resulting in the overactivation of cGAS-STING signaling to generate IFN-β [90][91]. Similarly, in SLE increased IFN-β generation affects various cells and organs such as blood, lung, interstitial, kidney, and skin [92][93][94]. Thus, the cGAS-STING signaling pathway in macrophages and T cell may serve as a connecting link between innate immunity and adaptive immunity [95].

4.3. Cancer

cGAS-STING signaling plays a crucial role in regulating various cancer subtypes. Suppression of STING activation in pancreatic cancer cells enhanced tumor size by reducing the infiltration of immune cells [96][97]. In mouse model of the breast cancer, cGAMP reduced tumor burden [98] and liposomal delivery of cGAMP also activated STING in the macrophages [99]. In syngeneic ovarian cancer (ID8) and colon cancer (CT26), poly (ADPribose) polymerase inhibitors (PARPi) increased IRF3 and STING activity [100]. Grabosch et al. found that cisplatin reduced ovarian cancer growth by increasing type I IFN production and inflammation [101]. Xie et al., 2019 found that tumor-associated mutations, G303E and K432T in h-cGAS [102] induced uterine endometrioid carcinoma by suppressing cGAMP generation [103].
Mechanistically, in the tumor microenvironment, STING is widely expressed in multiple cell types such as dendritic cells, myeloid cells, and endothelial cells [104][105][106] and serves as an important pathway for tumor-associated antigen presentation and regression of the tumor in mouse tumor models [107]. Unlike normal cells, cancer cells possess unstable genomes which undergo chromosome mis segregation during mitosis. The consequence of such segregation is the defective generation of micronuclei and their rupture that releases their genomic contents into the cytosol, resulting in activation of the cGAS-STING pathway [86][108][109][110]. Thus, mtDNA from ruptured micronuclei but not cytosolic DNA stimulates the cGAS-STING pathway in cancer. Oxidative stress in cancer cells is the primary mechanism to increase the porosity of the mitochondrial membrane leading to the export of mtDNA in the cytosol [35][111][112]. Indeed, the tumor cells are deprived of mtDNA and import it through exosomal transfer from host cells to restore mitochondrial function which enhances metastatic potential [113][114]. Thus, activation of cGAS-STING, through mtDNA and/or dsDNA, in cancer cells may serve as a checkpoint to the initial progression of neoplasm by the secretion of Type 1 IFNs inflammatory genes. Alternatively, it leads to the release of various other pro-inflammatory cytokines, chemokines, proteases, and growth factors. Collectively these various factors are called senescence-associated secretory phenotype (SASP) and have played a major role in the restriction of tumorigenesis [115][116][117]. Therefore, the STING activation in cancer cells suppresses its growth and/or recruits immune cells to clear cancer cells [115][118][119].
Antigen-presenting cells (APCs), such as dendritic cells (DCs) and macrophages, are thought to clear necrotic malignant cells [120][121]. DNA from tumor cells is also inserted into the immune cells such as macrophages and dendritic cells, however, the mechanism of DNA insertion inside the immune cells is not known [107]. Some studies suggest that ATP-gated P2X7 receptors are involved in the delivery of DNA to tumor- associate-macrophages (TAMs) to activate STING signaling in immune cells and enhance the tumor-antigen presentation into the CD8 T cells for their proliferation and cytotoxicity activity [107][122][123]. Activation of STING-signaling in TAM is associated with the polarization of TAM into the M1 stage and suppressing its tumor progressing activity. cGAMP generated into the tumor cells is transported into the host immune cells by SLC19A1, a folate transporter [124], which in turn activates STING-IRF3 signaling in immune cells to induce its tumoricidal activity such as in NK-cells [103].
Studies by various group showed that direct injection of STING agonist into the tumor microenvironment also decrease the suppressive Foxp3+ Treg protein in association with CD8+ T cell activation. DCs in the tumor microenvironment mostly respond to the tumor cells generated cGAMP to activate STING signaling. However, other cells may also respond such as fibroblast cells to inhibit tumor growth [122].
Taken together, cGAS-STING activation in the tumor microenvironment is important for anti-tumor activity and its regression. However, uncontrolled activation of the cGAS-STING pathway can promote angiogenesis due to excessive release of type I IFNs, chemokines, and growth factors [125].

4.4. Role of cGAS in Other Diseases

cGAS activation also causes other diseases, including neurological and macular degeneration and liver and renal diseases. Several excellent research discussed these topics [126][127][128][129][130][131][132][133].
In the brain, microglia are the principal cells that generate cGAS-STING dependent type-I interferon [127].
However, excessive cGAS activation leads to microglial pyroptosis after viral infection, trauma, stroke, and subarachnoid hemorrhage causing chronic neurodegenerative diseases [127][132]. Moreover, aging is a crucial factor in precipitating neurological disorders via augmenting cGAS-STING signaling and generation of aged diploid fibroblast cells [127][134][135][136]. 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 [133][135][137][138].
In the liver, malfunctioning of kupffer cells or monocytes-derived macrophages and hepatocytes is linked with mtDNA release and cGAS activity causes various liver diseases including hepatic ischemia-reperfusion injury, and hepatic cancer [126][128][139][140]. In this context, Luther’s lab showed that connexin-32 expression in hepatic parenchyma is a significant regulator of cGAS-induced type-I interferon synthesis in alcoholic liver diseases [141]. Iron accumulation in hepatic cells and metabolic stress also activated cGAS-STING signaling resulting in an inflammatory liver [142].
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 [131][143]. Cell death occurring from post-drug-induced nephrotoxicity, diabetic nephropathy, and ischemia-induced renal injury also activated cGAS-STING activation in the renal tubules [133]. 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.

This entry is adapted from the peer-reviewed paper 10.3390/cells11182812

References

  1. Ahn, J.; Barber, G.N. Self-DNA, STING-dependent signaling and the origins of autoinflammatory disease. Curr. Opin. Immunol. 2014, 31, 121–126.
  2. Janeway, C.A., Jr.; Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 2002, 20, 197–216.
  3. Kawai, T.; Akira, S. The role of pattern-recognition receptors in innate immunity: Update on Toll-like receptors. Nat. Immunol. 2010, 11, 373–384.
  4. Sun, L.; Wu, J.; Du, F.; Chen, X.; Chen, Z.J. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 2013, 339, 786–791.
  5. Li, Q.; Tian, S.; Liang, J.; Fan, J.; Lai, J.; Chen, Q. Therapeutic Development by Targeting the cGAS-STING Pathway in Autoimmune Disease and Cancer. Front. Pharmacol. 2021, 12, 779425.
  6. Hopfner, K.P.; Hornung, V. Molecular mechanisms and cellular functions of cGAS-STING signalling. Nat. Rev. Mol. Cell Biol. 2020, 21, 501–521.
  7. George, R.D.; McVicker, G.; Diederich, R.; Ng, S.B.; MacKenzie, A.P.; Swanson, W.J.; Shendure, J.; Thomas, J.H. Trans genomic capture and sequencing of primate exomes Rev..eals new targets of positive selection. Genome. Res. 2011, 21, 1686–1694.
  8. Hancks, D.C.; Hartley, M.K.; Hagan, C.; Clark, N.L.; Elde, N.C. Overlapping Patterns of Rapid Evolution in the Nucleic Acid Sensors cGAS and OAS1 Suggest a Common Mechanism of Pathogen Antagonism and Escape. PLoS Genet. 2015, 11, e1005203.
  9. Ma, Z.; Jacobs, S.R.; West, J.A.; Stopford, C.; Zhang, Z.; Davis, Z.; Barber, G.N.; Glaunsinger, B.A.; Dittmer, D.P.; Damania, B. Modulation of the cGAS-STING DNA sensing pathway by gammaherpesviruses. Proc. Natl. Acad. Sci. USA 2015, 112, E4306–E4315.
  10. Chen, H.-Y.; Pang, X.-Y.; Xu, Y.-Y.; Zhou, G.-P.; Xu, H.-G. Transcriptional regulation of human cyclic GMP-AMP synthase gene. Cell. Signal. 2019, 62, 109355.
  11. Wu, M.-Z.; Cheng, W.-C.; Chen, S.-F.; Nieh, S.; O’Connor, C.; Liu, C.-L.; Tsai, W.-W.; Wu, C.-J.; Martin, L.; Lin, Y.-S. miR-25/93 mediates hypoxia-induced immunosuppression by repressing cGAS. Nat. Cell Biol. 2017, 19, 1286–1296.
  12. Song, B.; Greco, T.M.; Lum, K.K.; Taber, C.E.; Cristea, I.M. The DNA Sensor cGAS is Decorated by Acetylation and Phosphorylation Modifications in the Context of Immune Signaling. Mol. Cell Proteom. 2020, 19, 1193–1208.
  13. Li, T.; Huang, T.; Du, M.; Chen, X.; Du, F.; Ren, J.; Chen, Z.J. Phosphorylation and chromatin tethering prevent cGAS activation during mitosis. Science 2021, 371, 1204.
  14. Seo, G.J.; Yang, A.; Tan, B.; Kim, S.; Liang, Q.; Choi, Y.; Yuan, W.; Feng, P.; Park, H.S.; Jung, J.U. Akt Kinase-Mediated Checkpoint of cGAS DNA Sensing Pathway. Cell Rep. 2015, 13, 440–449.
  15. Zhong, L.; Hu, M.M.; Bian, L.J.; Liu, Y.; Chen, Q.; Shu, H.B. Phosphorylation of cGAS by CDK1 impairs self-DNA sensing in mitosis. Cell Discov. 2020, 6, 26.
  16. Li, M.; Shu, H.B. Dephosphorylation of cGAS by PPP6C impairs its substrate binding activity and innate antiviral response. Protein Cell 2020, 11, 584–599.
  17. Liu, H.; Zhang, H.; Wu, X.; Ma, D.; Wu, J.; Wang, L.; Jiang, Y.; Fei, Y.; Zhu, C.; Tan, R.; et al. Nuclear cGAS suppresses DNA repair and promotes tumorigenesis. Nature 2018, 563, 131–136.
  18. Seo, G.J.; Kim, C.; Shin, W.J.; Sklan, E.H.; Eoh, H.; Jung, J.U. TRIM56-mediated monoubiquitination of cGAS for cytosolic DNA sensing. Nat. Commun. 2018, 9, 613.
  19. Liu, Z.S.; Zhang, Z.Y.; Cai, H.; Zhao, M.; Mao, J.; Dai, J.; Xia, T.; Zhang, X.M.; Li, T. RINCK-mediated monoubiquitination of cGAS promotes antiviral innate immune responses. Cell Biosci. 2018, 8, 35.
  20. Wang, Q.; Huang, L.; Hong, Z.; Lv, Z.; Mao, Z.; Tang, Y.; Kong, X.; Li, S.; Cui, Y.; Liu, H.; et al. The E3 ubiquitin ligase RNF185 facilitates the cGAS-mediated innate immune response. PLoS Pathog. 2017, 13, e1006264.
  21. Kato, Y.; Park, J.; Takamatsu, H.; Konaka, H.; Aoki, W.; Aburaya, S.; Ueda, M.; Nishide, M.; Koyama, S.; Hayama, Y.; et al. Apoptosis-derived membrane vesicles drive the cGAS-STING pathway and enhance type I IFN production in systemic lupus erythematosus. Ann. Rheum. Dis. 2018, 77, 1507–1515.
  22. Chen, M.; Meng, Q.; Qin, Y.; Liang, P.; Tan, P.; He, L.; Zhou, Y.; Chen, Y.; Huang, J.; Wang, R.F.; et al. TRIM14 Inhibits cGAS Degradation Mediated by Selective Autophagy Receptor p62 to Promote Innate Immune Responses. Mol. Cell 2016, 64, 105–119.
  23. Guo, Y.; Jiang, F.; Kong, L.; Li, B.; Yang, Y.; Zhang, L.; Liu, B.; Zheng, Y.; Gao, C. Cutting Edge: USP27X DeubiquitiNat.es and Stabilizes the DNA Sensor cGAS to Regulate Cytosolic DNA-Mediated Signaling. J. Immunol. 2019, 203, 2049–2054.
  24. Hu, M.M.; Yang, Q.; Xie, X.Q.; Liao, C.Y.; Lin, H.; Liu, T.T.; Yin, L.; Shu, H.B. Sumoylation Promotes the Stability of the DNA Sensor cGAS and the Adaptor STING to Regulate the Kinetics of Response to DNA Virus. Immunity 2016, 45, 555–569.
  25. Karayel, E. Zhang, Q.; Tang, Z.; An, R.; Ye, L.; Zhong, B. USP29 maintains the stability of cGAS and promotes cellular antiviral responses and autoimmunity. Cell Res. 2020, 30, 914–927.
  26. Cui, Y.; Yu, H.; Zheng, X.; Peng, R.; Wang, Q.; Zhou, Y.; Wang, R.; Wang, J.; Qu, B.; Shen, N.; et al. SENP7 Potentiates cGAS Activation by Relieving SUMO-Mediated Inhibition of Cytosolic DNA Sensing. PLoS Pathog. 2017, 13, e1006156.
  27. Narita, T.; Weinert, B.T.; Choudhary, C. Functions and mechanisms of non-histone protein acetylation. Nat. Rev. Mol. Cell Biol. 2019, 20, 156–174.
  28. Dai, J.; Huang, Y.J.; He, X.; Zhao, M.; Wang, X.; Liu, Z.S.; Xue, W.; Cai, H.; Zhan, X.Y.; Huang, S.Y.; et al. Acetylation Blocks cGAS Activity and Inhibits Self-DNA-Induced Autoimmunity. Cell 2019, 176, 1447–1460.e1414.
  29. Song, Z.M.; Lin, H.; Yi, X.M.; Guo, W.; Hu, M.M.; Shu, H.B. KAT5 acetylates cGAS to promote innate immune response to DNA virus. Proc. Natl Acad. Sci. USA 2020, 117, 21568–21575.
  30. Zierhut, C.; Yamaguchi, N.; Paredes, M.; Luo, J.-D.; Carroll, T.; Funabiki, H. The cytoplasmic DNA sensor cGAS promotes mitotic cell death. Cell 2019, 178, 302–315.e323.
  31. Barber, G.N. STING: Infection, inflammation and cancer. Nat. Rev. Immunol. 2015, 15, 760–770.
  32. Place, D.E.; Kanneganti, T.-D. Cell death–mediated cytokine release and its therapeutic implications. J. Exp. Med. 2019, 216, 1474–1486.
  33. Kuang, S.; Zheng, J.; Yang, H.; Li, S.; Duan, S.; Shen, Y.; Ji, C.; Gan, J.; Xu, X.-W.; Li, J. Structure insight of GSDMD reveals the basis of GSDMD autoinhibition in cell pyroptosis. Proc. Natl. Acad. Sci. USA 2017, 114, 10642–10647.
  34. Liu, X.; Zhang, Z.; Ruan, J.; Pan, Y.; Magupalli, V.G.; Wu, H.; Lieberman, J. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 2016, 535, 153–158.
  35. Huang, L.S.; Hong, Z.; Wu, W.; Xiong, S.; Zhong, M.; Gao, X.; Rehman, J.; Malik, A.B. mtDNA activates cGAS signaling and suppresses the YAP-mediated endothelial cell proliferation program to promote inflammatory injury. Immunity 2020, 52, 475–486.e475.
  36. Díaz-García, E.; García-Tovar, S.; Alfaro, E.; Jaureguizar, A.; Casitas, R.; Sánchez-Sánchez, B.; Zamarrón, E.; Fernández-Lahera, J.; López-Collazo, E.; Cubillos-Zapata, C. Inflammasome activation: A keystone of proinflammatory response in obstructive sleep apnea. Am. J. Respir. Crit. Care Med. 2022, 205, 1337–1348.
  37. Barnett, K.C.; Coronas-Serna, J.M.; Zhou, W.; Ernandes, M.J.; Cao, A.; Kranzusch, P.J.; Kagan, J.C. Phosphoinositide Interactions Position cGAS at the Plasma Membrane to Ensure Efficient Distinction between Self- and Viral DNA. Cell 2019, 176, 1432–1446.e1411.
  38. Zhang, W.; Zhou, Q.; Xu, W.; Cai, Y.; Yin, Z.; Gao, X.; Xiong, S. DNA-dependent activator of interferon-regulatory factors (DAI) promotes lupus nephritis by activating the calcium pathway. J. Biol. Chem. 2013, 288, 13534–13550.
  39. Berridge, M.J.; Lipp, P.; Bootman, M.D. The versatility and universality of calcium signalling. Nat. Rev. Mol. Cell. Biol. 2000, 1, 11–21.
  40. Wang, L.; Tassiulas, I.; Park-Min, K.H.; Reid, A.C.; Gil-Henn, H.; Schlessinger, J.; Baron, R.; Zhang, J.J.; Ivashkiv, L.B. “Tuning” of type I interferon-induced Jak-STAT1 signaling by calcium-dependent kinases in macrophages. Nat. Immunol. 2008, 9, 186–193.
  41. Tano, J.Y.; Vazquez, G. Requirement for non-regulated, constitutive calcium influx in macrophage survival signaling. Biochem. Biophys. Res. Commun. 2011, 407, 432–437.
  42. Srikanth, S.; Woo, J.S.; Wu, B.; El-Sherbiny, Y.M.; Leung, J.; Chupradit, K.; Rice, L.; Seo, G.J.; Calmettes, G.; Ramakrishna, C. The Ca2+ sensor STIM1 regulates the type I interferon response by retaining the signaling adaptor STING at the endoplasmic reticulum. Nat. Immunol. 2019, 20, 152–162.
  43. Kyttaris, V.C.; Zhang, Z.; Kampagianni, O.; Tsokos, G.C. Calcium signaling in systemic lupus erythematosus T cells: A treatment target. Arthritis Rheumatism. 2011, 63, 2058–2066.
  44. Mathavarajah, S.; Salsman, J.; Dellaire, G. An emerging role for calcium signalling in innate and autoimmunity via the cGAS-STING axis. Cytokine Growth Factor Rev. 2019, 50, 43–51.
  45. Smith, S.; Jefferies, C. Role of DNA/RNA sensors and contribution to autoimmunity. Cytokine Growth Factor Rev. 2014, 25, 745–757.
  46. Srivastava, N.; Tauseef, M.; Amin, R.; Joshi, B.; Joshi, J.C.; Kini, V.; Klomp, J.; Li, W.; Knezevic, N.; Barbera, N.; et al. Noncanonical function of long myosin light chain kinase in increasing ER-PM junctions and augmentation of SOCE. FASEB J. 2020, 34, 12805–12819.
  47. Yazbeck, P.; Tauseef, M.; Kruse, K.; Amin, M.R.; Sheikh, R.; Feske, S.; Komarova, Y.; Mehta, D. STIM1 Phosphorylation at Y361 Recruits Orai1 to STIM1 Puncta and Induces Ca(2+) Entry. Sci. Rep. 2017, 7, 42758.
  48. Soni, D.; Regmi, S.C.; Wang, D.-M.; DebRoy, A.; Zhao, Y.-Y.; Vogel, S.M.; Malik, A.B.; Tiruppathi, C. Pyk2 phosphorylation of VE-PTP downstream of STIM1-induced Ca2+ entry regulates disassembly of adherens junctions. Am. J. Physiol. -Lung Cell. Mol. Physiol. 2017, 312, L1003–L1017.
  49. Rayees, S.; Joshi, J.C.; Tauseef, M.; Anwar, M.; Baweja, S.; Rochford, I.; Joshi, B.; Hollenberg, M.D.; Reddy, S.P.; Mehta, D. PAR2-Mediated cAMP Generation Suppresses TRPV4-Dependent Ca(2+) Signaling in Alveolar Macrophages to Resolve TLR4-Induced Inflammation. Cell Rep. 2019, 27, 793–805.e794.
  50. Hurley, R.L.; Anderson, K.A.; Franzone, J.M.; Kemp, B.E.; Means, A.R.; Witters, L.A. The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases. J. Biol. Chem. 2005, 280, 29060–29066.
  51. Prantner, D.; Darville, T.; Nagarajan, U.M. Stimulator of IFN gene is critical for induction of IFN-beta during Chlamydia muridarum infection. J. Immunol. 2010, 184, 2551–2560.
  52. Konno, H.; Konno, K.; Barber, G.N. Cyclic dinucleotides trigger ULK1 (ATG1) phosphorylation of STING to prevent sustained innate immune signaling. Cell 2013, 155, 688–698.
  53. Kwon, D.; Sesaki, H.; Kang, S.J. Intracellular calcium is a rheostat for the STING signaling pathway. Biochem. Biophys. Res. Commun. 2018, 500, 497–503.
  54. Son, A.; de Jesus, A.A.; Schwartz, D.M. STIM1 holds a STING in its (N-terminal) tail. Cell Calcium 2019, 80, 192–193.
  55. Matthay, M.A.; Zemans, R.L. The acute respiratory distress syndrome: Pathogenesis and treatment. Annu. Rev. Pathol. 2011, 6, 147–163.
  56. Joshi, J.C.; Joshi, B.; Rochford, I.; Rayees, S.; Akhter, M.Z.; Baweja, S.; Chava, K.R.; Tauseef, M.; Abdelkarim, H.; Natarajan, V.; et al. SPHK2-Generated S1P in CD11b(+) Macrophages Blocks STING to Suppress the Inflammatory Function of Alveolar Macrophages. Cell Rep. 2020, 30, 4096–4109.e4095.
  57. Bellani, G.; Laffey, J.G.; Pham, T.; Fan, E.; Brochard, L.; Esteban, A.; Gattinoni, L.; van Haren, F.; Larsson, A.; McAuley, D.F.; et al. Epidemiology, Patterns of Care, and Mortality for Patients with Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries. JAMA 2016, 315, 788–800.
  58. Rochford, I.; Joshi, J.C.; Rayees, S.; Anwar, M.; Akhter, M.Z.; Yalagala, L.; Banerjee, S.; Mehta, D. Evidence for reprogramming of monocytes into reparative alveolar macrophages in vivo by targeting PDE4b. Am. J. Physiol. Lung Cell Mol. Physiol. 2021, 321, L686–L702.
  59. Bachmaier, K.; Stuart, A.; Singh, A.; Mukhopadhyay, A.; Chakraborty, S.; Hong, Z.; Wang, L.; Tsukasaki, Y.; Maienschein-Cline, M.; Ganesh, B.B.; et al. Albumin Nanoparticle Endocytosing Subset of Neutrophils for Precision Therapeutic Targeting of Inflammatory Tissue Injury. ACS Nano 2022, 16, 4084–4101.
  60. Leseigneur, C.; Le-Bury, P.; Pizarro-Cerda, J.; Dussurget, O. Emerging Evasion Mechanisms of Macrophage Defenses by Pathogenic Bacteria. Front. Cell Infect. Microbiol. 2020, 10, 577559.
  61. Korns, D.; Frasch, S.C.; Fernandez-Boyanapalli, R.; Henson, P.M.; Bratton, D.L. Modulation of macrophage efferocytosis in inflammation. Front. Immunol. 2011, 2, 57.
  62. Elliott, M.R.; Koster, K.M.; Murphy, P.S. Efferocytosis Signaling in the Regulation of Macrophage Inflammatory Responses. J. Immunol. 2017, 198, 1387–1394.
  63. Funes, S.C.; Rios, M.; Escobar-Vera, J.; Kalergis, A.M. Implications of macrophage polarization in autoimmunity. Immunol. Ogy. 2018, 154, 186–195.
  64. Mosser, D.M.; Edwards, J.P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 2008, 8, 958–969.
  65. Galbraith, M.D.; Kinning, K.T.; Sullivan, K.D.; Araya, P.; Smith, K.P.; Granrath, R.E.; Shaw, J.R.; Baxter, R.; Jordan, K.R.; Russell, S.; et al. Specialized interferon action in COVID-19. Proc. Natl. Acad Sci. USA 2022, 119, e2116730119.
  66. Decout, A.; Katz, J.D.; Venkatraman, S.; Ablasser, A. The cGAS-STING pathway as a therapeutic target in inflammatory diseases. Nat. Rev. Immunol. 2021, 21, 548–569.
  67. Lucas, C.; Wong, P.; Klein, J.; Castro, T.B.R.; Silva, J.; Sundaram, M.; Ellingson, M.K.; Mao, T.; Oh, J.E.; Israelow, B.; et al. Longitudinal analyses reveal immunological misfiring in severe COVID-19. Nature 2020, 584, 463–469.
  68. Nienhold, R.; Ciani, Y.; Koelzer, V.H.; Tzankov, A.; Haslbauer, J.D.; Menter, T.; Schwab, N.; Henkel, M.; Frank, A.; Zsikla, V.; et al. Two distinct immunopathological profiles in autopsy lungs of COVID-19. Nat. Commun. 2020, 11, 5086.
  69. Park, A.; Iwasaki, A. Type I and Type III Interferons—Induction, Signaling, Evasion, and Application to Combat COVID-19. Cell Host Microbe. 2020, 27, 870–878.
  70. Hadjadj, J.; Yatim, N.; Barnabei, L.; Corneau, A.; Boussier, J.; Smith, N.; Pere, H.; Charbit, B.; Bondet, V.; Chenevier-Gobeaux, C.; et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science 2020, 369, 718–724.
  71. Schulte-Schrepping, J.; Reusch, N.; Paclik, D.; Bassler, K.; Schlickeiser, S.; Zhang, B.; Kramer, B.; Krammer, T.; Brumhard, S.; Bonaguro, L.; et al. Severe COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment. Cell 2020, 182, 1419–1440.e1423.
  72. Rice, G.I.; Forte, G.M.; Szynkiewicz, M.; Chase, D.S.; Aeby, A.; Abdel-Hamid, M.S.; Ackroyd, S.; Allcock, R.; Bailey, K.M.; Balottin, U.; et al. Assessment of interferon-related biomarkers in Aicardi-Goutieres syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: A case-control study. Lancet. Neurol. 2013, 12, 1159–1169.
  73. Israelow, B.; Song, E.; Mao, T.; Lu, P.; Meir, A.; Liu, F.; Alfajaro, M.M.; Wei, J.; Dong, H.; Homer, R.J. Mouse model of SARS-CoV-2 Reveals inflammatory role of type I interferon signaling. J. Exp. Med. 2020, 217, e20201241.
  74. Domizio, J.D.; Gulen, M.F.; Saidoune, F.; Thacker, V.V.; Yatim, A.; Sharma, K.; Nass, T.; Guenova, E.; Schaller, M.; Conrad, C. The cGAS–STING pathway drives type I IFN immunopathology in COVID-19. Nature 2022, 603, 145–151.
  75. Heuberger, J.; Trimpert, J.; Vladimirova, D.; Goosmann, C.; Lin, M.; Schmuck, R.; Mollenkopf, H.J.; Brinkmann, V.; Tacke, F.; Osterrieder, N. Epithelial response to IFN-γ promotes SARS-CoV-2 infection. EMBO Mol. Med. 2021, 13, e13191.
  76. Akamatsu, H.; Toi, Y.; Hayashi, H.; Fujimoto, D.; Tachihara, M.; Furuya, N.; Otani, S.; Shimizu, J.; Katakami, N.; Azuma, K. Efficacy of Osimertinib Plus Bevacizumab vs Osimertinib in Patients With EGFR T790M–Mutated Non–Small Cell Lung Cancer PRev..iously Treated With Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitor: West Japan Oncology Group 8715L Phase 2 Randomized Clinical Trial. JAMA Oncol. 2021, 7, 386–394.
  77. Bueno, M.; Zank, D.; Buendia-Roldan, I.; Fiedler, K.; Mays, B.G.; Alvarez, D.; Sembrat, J.; Kimball, B.; Bullock, J.K.; Martin, J.L.; et al. PINK1 attenuates mtDNA release in alveolar epithelial cells and TLR9 mediated profibrotic responses. PLoS ONE 2019, 14, e0218003.
  78. Schuliga, M.; Pechkovsky, D.V.; Read, J.; Waters, D.W.; Blokland, K.E.C.; Reid, A.T.; Hogaboam, C.M.; Khalil, N.; Burgess, J.K.; Prele, C.M.; et al. Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts. J. Cell. Mol. Med. 2018, 22, 5847–5861.
  79. Schuliga, M.; Read, J.; Blokland, K.E.C.; Waters, D.W.; Burgess, J.; Prele, C.; Mutsaers, S.E.; Jaffar, J.; Westall, G.; Reid, A.; et al. Self DNA perpetuates IPF lung fibroblast senescence in a cGAS-dependent manner. Clin. Sci. (Lond.) 2020, 134, 889–905.
  80. da Silva, A.L.; Bresciani, M.J.; Karnopp, T.E.; Weber, A.F.; Ellwanger, J.H.; Henriques, J.A.; Valim, A.R.; Possuelo, L.G. DNA damage and cellular abnormalities in tuberculosis, lung cancer and chronic obstructive pulmonary disease. Multidiscip. Respir. Med. 2015, 10, 38.
  81. Maluf, S.W.; Mergener, M.; Dalcanale, L.; Costa, C.C.; Pollo, T.; Kayser, M.; da Silva, L.B.; Pra, D.; Teixeira, P.J.Z. DNA damage in peripheral blood of patients with chronic obstructive pulmonary disease (COPD). Mutat. Res. 2007, 626, 180–184.
  82. Zhou, J.; Chu, H.; Li, C.; Wong, B.H.-Y.; Cheng, Z.-S.; Poon, V.K.-M.; Sun, T.; Lau, C.C.-Y.; Wong, K.K.-Y.; Chan, J.Y.-W.; et al. Active replication of Middle East respiratory syndrome coronavirus and aberrant induction of inflammatory cytokines and chemokines in human macrophages: Implications for pathogenesis. J. Infect. Dis. 2014, 209, 1331–1342.
  83. Channappanavar, R.; Fehr, A.R.; Zheng, J.; Wohlford-Lenane, C.; Abrahante, J.E.; Mack, M.; Sompallae, R.; McCray, P.B.; Meyerholz, D.K.; Perlman, S. IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes. J. Clin. Investig. 2019, 129, 3625–3639.
  84. Guerriero, J.L. Macrophages: Their Untold Story in T Cell Activation and Function. Int. Rev. Cell Mol. Biol. 2019, 342, 73–93.
  85. Bergsmedh, A.; Szeles, A.; Henriksson, M.; Bratt, A.; Folkman, M.J.; Spetz, A.L.; Holmgren, L. Horizontal transfer of oncogenes by uptake of apoptotic bodies. Proc. Natl. Acad. Sci. USA 2001, 98, 6407–6411.
  86. Kwon, J.; Bakhoum, S.F. The Cytosolic DNA-Sensing cGAS-STING Pathway in Cancer. Cancer Discov. 2020, 10, 26–39.
  87. Wang, Y.; Wang, F.; Zhang, X. STING-associated vasculopathy with onset in infancy: A familial case series report and literature Review. Ann. Transl. Med. 2021, 9, 176.
  88. Cuadrado, E.; Michailidou, I.; van Bodegraven, E.J.; Jansen, M.H.; Sluijs, J.A.; Geerts, D.; Couraud, P.O.; De Filippis, L.; Vescovi, A.L.; Kuijpers, T.W.; et al. Phenotypic variation in Aicardi-Goutieres syndrome explained by cell-specific IFN-stimulated gene response and cytokine release. J. Immunol. 2015, 194, 3623–3633.
  89. Crow, Y.J.; Hayward, B.E.; Parmar, R.; Robins, P.; Leitch, A.; Ali, M.; Black, D.N.; van Bokhoven, H.; Brunner, H.G.; Hamel, B.C.; et al. Mutations in the gene encoding the 3’-5’ DNA exonuclease TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus. Nat. Genet. 2006, 38, 917–920.
  90. Yan, N. Immune Diseases Associated with TREX1 and STING Dysfunction. J. Interferon Cytokine Res. 2017, 37, 198–206.
  91. Stetson, D.B.; Ko, J.S.; Heidmann, T.; Medzhitov, R. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell 2008, 134, 587–598.
  92. Lundgren, M.C.; Molitor, J.A.; Spilseth, B.; Adeyi, O. A Fatal Case of Diffuse Alveolar Hemorrhage in the Setting of Systemic Lupus Erythematosus: A Case Report and Review of Noninfectious Causes of Acute Pulmonary Hemorrhage in Adults. Case Rep. Rheumatol. 2021, 2021, 6620701.
  93. Hepburn, A.L.; Narat, S.; Mason, J.C. The management of peripheral blood cytopenias in systemic lupus erythematosus. Rheumatology 2010, 49, 2243–2254.
  94. Knight, J.S.; Subramanian, V.; O’Dell, A.A.; Yalavarthi, S.; Zhao, W.; Smith, C.K.; Hodgin, J.B.; Thompson, P.R.; Kaplan, M.J. Peptidylarginine deiminase inhibition disrupts NET formation and protects against kidney, skin and vascular disease in lupus-prone MRL/lpr mice. Ann. Rheum. Dis. 2015, 74, 2199–2206.
  95. Zheng, J.; Mo, J.; Zhu, T.; Zhuo, W.; Yi, Y.; Hu, S.; Yin, J.; Zhang, W.; Zhou, H.; Liu, Z. Comprehensive elaboration of the cGAS-STING signaling axis in cancer development and immunotherapy. Mol. Cancer 2020, 19, 133.
  96. Takashima, K.; Takeda, Y.; Oshiumi, H.; Shime, H.; Okabe, M.; Ikawa, M.; Matsumoto, M.; Seya, T. STING in tumor and host cells cooperatively work for NK cell-mediated tumor growth retardation. Biochem. Biophys. Res. Commun. 2016, 478, 1764–1771.
  97. Ho, S.S.W.; Zhang, W.Y.L.; Tan, N.Y.J.; Khatoo, M.; Suter, M.A.; Tripathi, S.; Cheung, F.S.G.; Lim, W.K.; Tan, P.H.; Ngeow, J.; et al. The DNA Structure-Specific Endonuclease MUS81 Mediates DNA Sensor STING-Dependent Host Rejection of Prostate Cancer Cells. Immunity 2016, 44, 1177–1189.
  98. Chen, Q.; Boire, A.; Jin, X.; Valiente, M.; Er, E.E.; Lopez-Soto, A.; Jacob, L.S.; Patwa, R.; Shah, H.; Xu, K.; et al. Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature 2016, 533, 493–498.
  99. Petrovic, M.; Borchard, G.; Jordan, O. Considerations for the delivery of STING ligands in cancer immunotherapy. J. Control. Release 2021, 339, 235–247.
  100. Shen, J.; Zhao, W.; Ju, Z.; Wang, L.; Peng, Y.; Labrie, M.; Yap, T.A.; Mills, G.B.; Peng, G. PARPi Triggers the STING-Dependent Immune Response and Enhances the Therapeutic Efficacy of Immune Checkpoint Blockade Independent of BRCAness. Cancer Res. 2019, 79, 311–319.
  101. Grabosch, S.; Bulatovic, M.; Zeng, F.; Ma, T.; Zhang, L.; Ross, M.; Brozick, J.; Fang, Y.; Tseng, G.; Kim, E.; et al. Cisplatin-induced immune modulation in ovarian cancer mouse models with distinct inflammation profiles. Oncogene 2019, 38, 2380–2393.
  102. Xie, W.; Lama, L.; Adura, C.; Tomita, D.; Glickman, J.F.; Tuschl, T.; Patel, D.J. Human cGAS catalytic domain has an additional DNA-binding interface that enhances enzymatic activity and liquid-phase condensation. Proc. Natl. Acad. Sci. USA 2019, 116, 11946–11955.
  103. Marcus, A.; Mao, A.J.; Lensink-Vasan, M.; Wang, L.; Vance, R.E.; Raulet, D.H. Tumor-Derived cGAMP Triggers a STING-Mediated Interferon Response in Non-tumor Cells to Activate the NK Cell Response. Immunity 2018, 49, 754–763.e754.
  104. Ohkuri, T.; Ghosh, A.; Kosaka, A.; Zhu, J.; Ikeura, M.; David, M.; Watkins, S.C.; Sarkar, S.N.; Okada, H. STING contributes to antiglioma immunity via triggering type I IFN signals in the tumor microenvironment. Cancer Immunol. Res. 2014, 2, 1199–1208.
  105. Klarquist, J.; Hennies, C.M.; Lehn, M.A.; Reboulet, R.A.; Feau, S.; Janssen, E.M. STING-mediated DNA sensing promotes antitumor and autoimmune responses to dying cells. J. Immunol. 2014, 193, 6124–6134.
  106. Demaria, O.; De Gassart, A.; Coso, S.; Gestermann, N.; Di Domizio, J.; Flatz, L.; Gaide, O.; Michielin, O.; Hwu, P.; Petrova, T.V.; et al. STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity. Proc. Natl. Acad. Sci. USA 2015, 112, 15408–15413.
  107. Woo, S.R.; Fuertes, M.B.; Corrales, L.; Spranger, S.; Furdyna, M.J.; Leung, M.Y.; Duggan, R.; Wang, Y.; Barber, G.N.; Fitzgerald, K.A.; et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 2014, 41, 830–842.
  108. Crasta, K.; Ganem, N.J.; Dagher, R.; Lantermann, A.B.; Ivanova, E.V.; Pan, Y.; Nezi, L.; Protopopov, A.; Chowdhury, D.; Pellman, D. DNA breaks and chromosome pulverization from errors in mitosis. Nature 2012, 482, 53–58.
  109. Harding, S.M.; Benci, J.L.; Irianto, J.; Discher, D.E.; Minn, A.J.; Greenberg, R.A. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature 2017, 548, 466–470.
  110. Mackenzie, K.J.; Carroll, P.; Martin, C.-A.; Murina, O.; Fluteau, A.; Simpson, D.J.; Olova, N.; Sutcliffe, H.; Rainger, J.K.; Leitch, A.; et al. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature 2017, 548, 461–465.
  111. Kitajima, S.; Ivanova, E.; Guo, S.; Yoshida, R.; Campisi, M.; Sundararaman, S.K.; Tange, S.; Mitsuishi, Y.; Thai, T.C.; Masuda, S.; et al. Suppression of STING Associated with LKB1 Loss in KRAS-Driven Lung Cancer. Cancer Discov. 2019, 9, 34–45.
  112. Platnich, J.M.; Chung, H.; Lau, A.; Sandall, C.F.; Bondzi-Simpson, A.; Chen, H.M.; Komada, T.; Trotman-Grant, A.C.; Brandelli, J.R.; Chun, J.; et al. Shiga Toxin/Lipopolysaccharide Activates Caspase-4 and Gasdermin D to Trigger Mitochondrial Reactive Oxygen Species Upstream of the NLRP3 Inflammasome. Cell Rep. 2018, 25, 1525–1536.e1527.
  113. Tan, X.; Sun, L.; Chen, J.; Chen, Z.J. Detection of Microbial Infections Through Innate Immune Sensing of Nucleic Acids. Annu. Rev. Microbiol. 2018, 72, 447–478.
  114. Sansone, P.; Savini, C.; Kurelac, I.; Chang, Q.; Amato, L.B.; Strillacci, A.; Stepanova, A.; Iommarini, L.; Mastroleo, C.; Daly, L.; et al. Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer. Proc. Natl Acad. Sci. USA 2017, 114, E9066–E9075.
  115. Dou, Z.; Ghosh, K.; Vizioli, M.G.; Zhu, J.; Sen, P.; Wangensteen, K.J.; Simithy, J.; Lan, Y.; Lin, Y.; Zhou, Z.; et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 2017, 550, 402–406.
  116. Yang, H.; Wang, H.; Ren, J.; Chen, Q.; Chen, Z.J. cGAS is essential for cellular senescence. Proc. Natl. Acad. Sci. USA 2017, 114, E4612–E4620.
  117. Coppe, J.P.; Patil, C.K.; Rodier, F.; Sun, Y.; Munoz, D.P.; Goldstein, J.; Nelson, P.S.; Desprez, P.Y.; Campisi, J. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008, 6, 2853–2868.
  118. Gluck, S.; Guey, B.; Gulen, M.F.; Wolter, K.; Kang, T.W.; Schmacke, N.A.; Bridgeman, A.; Rehwinkel, J.; Zender, L.; Ablasser, A. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat. Cell Biol. 2017, 19, 1061–1070.
  119. Ranoa, D.R.E.; Widau, R.C.; Mallon, S.; Parekh, A.D.; Nicolae, C.M.; Huang, X.; Bolt, M.J.; Arina, A.; Parry, R.; Kron, S.J.; et al. STING Promotes Homeostasis via Regulation of Cell Proliferation and Chromosomal Stability. Cancer Res. 2019, 79, 1465–1479.
  120. Sauter, B.; Albert, M.L.; Francisco, L.; Larsson, M.; Somersan, S.; Bhardwaj, N. Consequences of cell death: Exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells. J. Exp. Med. 2000, 191, 423–434.
  121. Smyth, M.J.; Godfrey, D.I.; Trapani, J.A. A fresh look at tumor immunosurveillance and immunotherapy. Nat. Immunol. 2001, 2, 293–299.
  122. Deng, L.; Liang, H.; Xu, M.; Yang, X.; Burnette, B.; Arina, A.; Li, X.D.; Mauceri, H.; Beckett, M.; Darga, T.; et al. STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors. Immunity 2014, 41, 843–852.
  123. Diamond, M.S.; Kinder, M.; Matsushita, H.; Mashayekhi, M.; Dunn, G.P.; Archambault, J.M.; Lee, H.; Arthur, C.D.; White, J.M.; Kalinke, U.; et al. Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J. Exp. Med. 2011, 208, 1989–2003.
  124. Ritchie, C.; Cordova, A.F.; Hess, G.T.; Bassik, M.C.; Li, L. SLC19A1 Is an Importer of the Immunotransmitter cGAMP. Mol. Cell 2019, 75, 372–381.e375.
  125. Nowarski, R.; Gagliani, N.; Huber, S.; Flavell, R.A. Innate immune cells in inflammation and cancer. Cancer Immunol. Res. 2013, 1, 77–84.
  126. Bao, T.; Liu, J.; Leng, J.; Cai, L. The cGAS-STING pathway: More than fighting against viruses and cancer. Cell Biosci. 2021, 11, 209.
  127. Fryer, A.L.; Abdullah, A.; Taylor, J.M.; Crack, P.J. The Complexity of the cGAS-STING Pathway in CNS Pathologies. Front. Neurosci. 2021, 15, 621501.
  128. Chen, B.; Rao, X.; Wang, X.; Luo, Z.; Wang, J.; Sheng, S.; Liu, Y.; Zhang, N.; Jin, S.; Chen, H.; et al. cGAS-STING Signaling Pathway and Liver Disease: From Basic Research to Clinical Practice. Front. Pharm. 2021, 12, 719644.
  129. Chen, R.; Du, J.; Zhu, H.; Ling, Q. The role of cGAS-STING signalling in liver diseases. JHEP Rep. 2021, 3, 100324.
  130. Jauhari, A.; Baranov, S.V.; Suofu, Y.; Kim, J.; Singh, T.; Yablonska, S.; Li, F.; Wang, X.; Oberly, P.; Minnigh, M.B.; et al. Melatonin inhibits cytosolic mitochondrial DNA—induced neuroinflammatory signaling in accelerated aging and neurodegeneration. J. Clin. Invest. 2020, 130, 3124–3136.
  131. Bai, J.; Liu, F. cGASSTING signaling and function in metabolism and kidney diseases. J. Mol. Cell Biol. 2021, 13, 728–738.
  132. Ding, R.; Li, H.; Liu, Y.; Ou, W.; Zhang, X.; Chai, H.; Huang, X.; Yang, W.; Wang, Q. Activating cGAS-STING axis contributes to neuroinflammation in CVST mouse model and induces inflammasome activation and microglia pyroptosis. J. Neuroinflamm. 2022, 19, 137.
  133. Skopelja-Gardner, S.; An, J.; Elkon, K.B. Role of the cGAS-STING pathway in systemic and organ-specific diseases. Nat. Rev. Nephrol. 2022, 18, 558–572.
  134. Barrett, J.P.; Knoblach, S.M.; Bhattacharya, S.; Gordish-Dressman, H.; Stoica, B.A.; Loane, D.J. Traumatic Brain Injury Induces cGAS Activation and Type I Interferon Signaling in Aged Mice. Front. Immunol. 2021, 12, 710608.
  135. Larrick, J.W.; Mendelsohn, A.R. Modulation of cGAS-STING Pathway by Nicotinamide Riboside in Alzheimer’s Disease. Rejuven. Res. 2021, 24, 397–402.
  136. Li, F.; Wang, N.; Zheng, Y.; Luo, Y.; Zhang, Y. cGAS- Stimulator of Interferon Genes Signaling in Central Nervous System Disorders. Aging. Dis. 2021, 12, 1658–1674.
  137. Jin, M.; Shiwaku, H.; Tanaka, H.; Obita, T.; Ohuchi, S.; Yoshioka, Y.; Jin, X.; Kondo, K.; Fujita, K.; Homma, H.; et al. activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation. Nat. Commun. 2021, 12, 6565.
  138. Paul, B.D.; Snyder, S.H.; Bohr, V.A. Signaling by cGAS-STING in Neurodegeneration, Neuroinflammation, and Aging. Trends Neurosci. 2021, 44, 83–96.
  139. Xu, D.; Tian, Y.; Xia, Q.; Ke, B. The cGAS-STING Pathway: Novel Perspectives in Liver Diseases. Front. Immunol. 2021, 12, 682736.
  140. Wang, X.; Rao, H.; Zhao, J.; Wee, A.; Li, X.; Fei, R.; Huang, R.; Wu, C.; Liu, F.; Wei, L. STING expression in monocyte-derived macrophages is associated with the progression of liver inflammation and fibrosis in patients with nonalcoholic fatty liver disease. Lab. Invest. 2020, 100, 542–552.
  141. Luther, J.; Khan, S.; Gala, M.K.; Kedrin, D.; Sridharan, G.; Goodman, R.P.; Garber, J.J.; Masia, R.; Diagacomo, E.; Adams, D.; et al. Hepatic gap junctions amplify alcohol liver injury by propagating cGAS-mediated IRF3 activation. Proc. Natl. Acad. Sci. USA 2020, 117, 11667–11673.
  142. Li, H.; Hu, L.; Wang, L.; Wang, Y.; Shao, M.; Chen, Y.; Wu, W.; Wang, L. Iron Activates cGAS-STING Signaling and Promotes Hepatic Inflammation. J. Agric. Food Chem. 2022, 70, 2211–2220.
  143. Chung, K.W.; Dhillon, P.; Huang, S.; Sheng, X.; Shrestha, R.; Qiu, C.; Kaufman, B.A.; Park, J.; Pei, L.; Baur, J.; et al. Mitochondrial Damage and Activation of the STING Pathway Lead to Renal Inflammation and Fibrosis. Cell Metab. 2019, 30, 784–799.e785.
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