The regulation of cGAS-STING signaling by RNA virus-derived components

cGAS, functioning as an innate immune sensor, possesses the capability to recognize a diverse array of cytosolic dsDNA, originating from viruses, bacteria, mitochondria, and micronuclei, which can be primarily categorized into pathogen-derived DNA and self-DNA [11, 12]. In addition to intracellular dsDNA and dsRNA, cytoplasmic RNA: DNA hybrids can directly activate cGAS, eliciting an effective antiviral immune response [13]. In instances such as simian virus 40 infection, slight DNA damage leakage fosters GAS recruitment and activation [14]. cGAS can also be involved in the detection of tissue damage/formation of DNA traps. After phagocytosis of neutrophil extracellular traps (NETs) by peripheral blood mononuclear cells (PBMCs), their DNA is transferred to the cytoplasm and cGAS is activated in the cytoplasm. Evidence of NETs activation of cGAS in vivo was also obtained in a model of autoimmune hepatitis induced by injection of the lectin concanavalin A [15, 16].

STING, discovered before cGAS, plays a critical role in DNA recognition and TLR9-independent IFN production [17‐19]. In the cytoplasm, cGAS undergoes activation through interaction with dsDNA, a process independent of DNA sequence but reliant on DNA length [20, 21]. Structural analyses have unveiled a distinctive zinc thumb in cGAS responsible for recognizing B-form dsDNA [22]. Activated cGAS catalyzed the ATP and GTP into 2′3′-cyclic GMP-AMP (2′3′-cGAMP) [23]. Then cGAMP bound to and activated STING in the endoplasmic reticulum, promoting tetramer formation of STING through the oligomerization and translocated to the ER-Golgi intermediate compartments [24, 25]. Afterwards, TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) are recruited by STING, followed by TBK1 autophosphorylation along with phosphorylation of STING and IRF3. The phosphorylated IRF3 dimerizes and localized to the nucleus to initiate IFN-I expression and subsequent induction of ISG expression, thereby instigating antiviral defense (Fig. 1) [6, 26]. Simultaneously, IRF7 and nuclear factor (NF-κB) are activated by TBK1, leading to the expression of other inflammatory cytokines [27, 28]. Notably, STING is also capable of directly detecting viral particles independent of cGAS [29].

Though most studies focused on its role in DNA virus infection, increasing evidence has confirmed that cGAS-STING signaling also participated in RNA virus infection [30, 31]. As a self-protective mechanism, multiple RNA virus-derived components have been reported to be involved in the regulation of cGAS-STING signaling, such as SARS-CoV-2-derived open reading frames, and non-structural proteins, HIV-1-derived Vif, and HCoV-NL63-derived Papin-like protease (PLP) [32‐35]. Thus, we will discuss the role of viral components in regulating cGAS-STING signaling in the following sections (Table 1).

Ongoing clinical trials of cGAS-STING signaling pathway primarily focused on antitumor immunity, whereas, due to growing evidence tapping into the potential of anti-viral immunity, making it a new strategy for the treatment of infections. Considering the pivotal roles of STING in viral infection, several studies have explored the function of STING agonists in therapy [31, 82‐84]. Diaminobenzimidazole (diABZI), a small-molecule STING agonist that induces rapid short-term activation of STING, has been reported to inhibit viral replication in infected cells (∼ 1000-fold inhibition) in an IFN-dependent manner [82]. Similar phenomena have been revealed in studies of other STING agonists. Given the inhibitory effect of SARS-CoV-2-dereived 3CL on STING, 3CL inhibitors (such as flavonoids and PF-00835231) have been widely used in the treatment of COVID-19 [85, 86]. Also, it might be promising in the treatment of other 3CL-containing virus-induced infection [87]. However, not all cases of cGAS-STING activation lead to ameliorating the symptoms. Researchers have found that excessive activation of cGAS-STING can exacerbate the virus-induced inflammatory factor storm, which may correlate with the poor prognosis of patients [88]. It has been shown that in different RNA virus-infected cells, immunological differences between viruses can result in different regulatory mechanisms of cGAS-STING. In a study by Christopher J Neufeldt et al., it was found that SARS-CoV-2 infection leads to a storm of inflammatory factors through selective activation of the cGAS-STING signaling axis and thus NF-κB. Inflammatory gene activation was reduced by 60–75% with STING inhibitors [88]. Similar phenomena have been observed in other plus-stranded RNA viruses such as flaviviruses, SARS-CoV and NL63 coronavirus [89]. Application of H-151, a STING inhibitor, attenuates SARS-CoV-2-induced severe lung inflammation and improves disease prognosis [10]. An alternative inhibitor of TBK1/IKKε signaling that disrupts TBK1/IKKε signaling and prevents phosphorylation of S172, thereby blocking IRF3 and STING-mediated NF-κB-mediated transcriptional programs, shows strength in limiting excessive inflammation in SARS-CoV-2 [90]. Thus, the exploration and improvement of STING agonists and protease inhibitors and how to avoid pathological activation of STING during treatment may be the future orientation of treatment. In addition, studies have shown that the cGAS-STING signaling pathway is closely related to a variety of diseases such as tumors, autoimmune diseases, cardiovascular diseases, metabolic diseases, and neurodegenerative diseases, and has great potential to enhance tumor immunity and improve diseases. Therefore, guiding the development of novel targeted drugs for cGAS-STING signaling pathway and taking it into account the safety and efficacy of diseases are also imminent.