The cGAS-cGAMP-STING Pathway: A Molecular Link Between Immunity and Metabolism

Abstract

It has been appreciated for many years that there is a strong association between metabolism and immunity in advanced metazoan organisms. Distinct immune signatures and signaling pathways have been found not only in immune but also in metabolic cells. The newly discovered DNA-sensing cGAS-cGAMP-STING pathway mediates type I interferon inflammatory responses in immune cells to defend against viral and bacterial infections. Recent studies show that this pathway is also activated by host DNA aberrantly localized in the cytosol, contributing to increased sterile inflammation, insulin resistance, and the development of nonalcoholic fatty liver disease (NAFLD). Potential interactions of the cGAS-cGAMP-STING pathway with mTORC1 signaling, autophagy, and apoptosis have been reported, suggesting an important role of the cGAS-cGAMP-STING pathway in the networking and coordination of these important biological processes. However, the regulation, mechanism of action, and tissue-specific role of the cGAS-cGAMP-STING signaling pathway in metabolic disorders remain largely elusive. It is also unclear whether targeting this signaling pathway is effective for the prevention and treatment of obesity-induced metabolic diseases. Answers to these questions would provide new insights for developing effective therapeutic interventions for metabolic diseases such as insulin resistance, NAFLD, and type 2 diabetes.

Figure 1

Activation and regulation of the cGAS-cGAMP-STING pathway in cells. The cGAS is activated by viral and bacterial DNA as well as mtDNA and phagocytosed DNA aberrantly localized in the cytosol. Activated cGAS uses ATP and GTP as substrates to catalyze the formation of the second messenger, cGAMP, which binds to STING localized on the ER membrane. The binding of cGAMP to STING promotes STING translocation to the Golgi apparatus. During the translocation, STING recruits and activates TBK1, which in turn catalyzes the phosphorylation and nuclear translocation of IRF3, and to a lesser extent NF-κB, which can also be activated by IKK, leading to increased synthesis of IFN and other inflammatory genes.

Figure 2

Activation of the cGAS-cGAMP-STING pathway mediates obesity-induced inflammation and metabolic disorders. Obesity reduces the expression levels of disulfide bond A oxidoreductase-like protein (DsbA-L) in adipose tissue, leading to mitochondrial stress and subsequent mtDNA release into the cytosol. Aberrant localization of mtDNA in the cytosol activates the cGAS-cGAMP-STING pathway, leading to enhanced inflammatory gene expression and insulin resistance. Phosphorylated and activated TBK1 exerts a feedback inhibitory role by promoting STING ubiquitination and degradation or stimulating phosphorylation-dependent degradation of NF-κB–inducing kinase (NIK), thus attenuating cGAS-cGAMP-STING–mediated inflammatory response.

Figure 3

The interplay between the cGAS-cGAMP-STING pathway with mTORC1 signaling. Knockout of three-prime repair exonuclease 1 (Trex1), which degrades DNA in the cytosol, leads to the activation of the cGAS-cGAMP-STING pathway and suppression of the mTORC1 activity in mice. The cGAS-cGAMP-STING pathway may inhibit mTORC1 activity through a TBK1-dependent mechanism. Conversely, the cGAS-cGAMP-STING pathway may be inhibited by mTORC1-dependent suppression of STING activity and IRF3 translocation or by mTORC2-mediated cGAS degradation. Of note, the kinase domain but not the kinase function of ribosomal protein S6 kinase 1 (S6K1) is essential for S6K to interact with STING, which facilitates TBK1-mediated phosphorylation of STING and recruitment of IRF3 for antiviral immune responses.

Figure 4

The cross talk between the cGAS-cGAMP-STING pathway and autophagy/mitophagy. Autophagy is initiated with the activation of ULK1 complex. ULK1-induced activation of beclin-1 complex favors the nucleation of autophagosome precursors and promotes autophagy. Mitophagy is a selective form of autophagy. Activation of the cGAS-cGAMP-STING pathway may stimulate autophagy via a cGAS/beclin-1 interaction–dependent mechanism. The cGAS-cGAMP-STING pathway also promotes autophagy/mitophagy by TBK1-dependent phosphorylation and activation of receptors OPTN and p62 (SQSTM). Alternatively, activation of the cGAS-cGAMP-STING pathway promotes an autophagy-dependent negative feedback regulation by 1) the interaction of cGAS with beclin-1, which in turn inhibits cGAS activity; 2) cGAMP-induced activation of ULK1, which promotes STING degradation by phosphorylation at Ser³⁶⁶; and 3) TBK1-p62/SQSTM1–dependent ubiquitination and degradation of STING. PINK/Parkin-induced mitophagy also restrains cGAS-cGAMP-STING signaling and innate immunity by mitophagy-mediated mtDNA clearance.

Figure 5

The association of cGAS-cGAMP-STING signaling with apoptosis. The activation of prodeath proteins such as Bax/Bak promotes mitochondrial outer-membrane permeabilization and the release of cytochrome c to the cytosol, leading to activation of intrinsic apoptosis through initiator and executioner caspases cascade. Defects in apoptosis by knocking out caspase-9 or caspase-3/-7 lead to constitutive activation of the cGAS-cGAMP-STING pathway; however, the precise mechanisms by which caspase-induced apoptosis inhibits innate immune remain unknown. Inflammatory caspases including caspase-1, which can be activated by mtDNA release–induced formation of inflammasome, or caspase-4, -5, and -11 cleave cGAS, thus preventing the activation of immune response. Alternatively, activation of the cGAS-cGAMP-STING pathway promotes apoptosis via both transcriptional and nontranscriptional programs in a TBK1-IRF3–dependent manner.