Regulation and function of the cGAS-MITA/STING axis in health and disease

Abstract

The innate immune systems detect pathogens via pattern-recognition receptors including nucleic acid sensors and non-nucleic acid sensors. Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS, also known as MB21D1) is a cytosolic DNA sensor that recognizes double-stranded DNA (dsDNA) and catalyzes the synthesis of 2',3'-cGAMP. Subsequently, 2',3'-cGAMP binds to the adaptor protein mediator of IRF3 activation (MITA, also known as STING, MPYS, ERIS, and TMEM173) to activate downstream signaling cascades. The cGAS-MITA/STING signaling critically mediates immune responses against DNA viruses, retroviruses, bacteria, and protozoan parasites. In addition, recent discoveries have extended our understanding of the roles of the cGAS-MITA/STING pathway in autoimmune diseases and cancers. Here, we summarize the identification and activation of cGAS and MITA/STING, present the updated functions and regulatory mechanisms of cGAS-MITA/STING signaling and provide a comprehensive understanding of the cGAS-MITA/STING axis in autoimmune diseases and cancers.

Keywords: Autoimmune diseases; Cancer; Innate immunity; MITA/STING; cGAS.

Fig. 1

The cGAS-MITA/STING pathway. The accumulation of cytosolic DNA is a mark of pathogen invasion. Cytosolic DNA sourced from DNA virus, damaged mitochondria, or reverse transcription of retroelements is detected by cGAS, leading to the formation of cGAS-DNA liquid droplets, in which cGAS, ATP, and GTP are concentrated to initiate the synthesis of cGAMP. MITA subsequently binds to cGAMP and undergoes dimerization and polymerization. Polymerized MITA encapsulated in SEC24C- mediated COPII vesicles translocates from the ER to Golgi via ERGIC, where MITA triggers autophagosome formation via LC3 lipidation, which leads to the clearance of cytosolic DNA and pathogens. At the Golgi apparatus, MITA undergoes palmitoylation and binds to sGAGs, which contributes to the recruitment of TBK1 and autophosphorylation of TBK1. TBK1 phosphorylates the C-terminal domains of MITA to recruit IRF3, after that IRF3 also is phosphorylated by TBK1 and translocates to the nucleus in a KPNA2-dependent manner, mediating the expression of type I IFNs. Moreover, MITA also activates NF-κB to mediate the expression of inflammatory genes. After the translocation process, MITA would be targeted to the lysosome for degradation and retrieve from Golgi back to the ER to avoid hyperactivation. cGAMP, 2′,3′-cyclic GMP-AMP; sGAG, sulfated glycosaminoglycans; IFN, interferon.

Fig. 2

Regulation of cGAS-MITA/STINGpathway in tumor suppression. In early neoplastic cells, the cGAS-MITA pathway plays a tumor-suppressive role. DNA damage sourced from such as oxidative stress, radiation, CIN, or cisplatin leads to DNA accumulate in the cytoplasm, which activates the cGAS and promotes the synthesis of cGAMP. On one hand, cGAMP binds to MITA to upregulate the expression of type I IFNs and SASP genes in tumors, which in turn mediates tumor-suppressive effects. On the other hand, the cGAS-MITA pathway could mediate the crosstalk between the tumor cells and DCs nearby. Tumor DNA or tumor-derived cGAMP could activate the cGAS-MITA signaling in DCs, finally initiating tumor clearance mediated by immune cells such as CD8⁺ T cells or NK cells. CIN, chromosomal instability; cGAMP, 2′,3′-cyclic GMP-AMP; IFN, interferon; SASP, senescence-associated secretory phenotype; DC, dendritic cell; NK cells, natural killer cells. IFN-R, IFN receptor.

Fig. 3

Regulation of cGAS-MITA/STING pathway in tumor promotion. The cGAS-MITA pathway exerts its function as a tumor promoter in metastatic tumor cells. Tumors carrying high chromosome instability could promote the formation of micronuclei, which ruptures and release DNA to the cytosol, triggering the activation of the cGAS-MITA signaling. Chronic activation of the pathway promotes the suppression of type I IFNs expression and initiates the upregulation of noncanonical NF-κB signaling, facilitating tumor metastasis. The IDO and pro-inflammatory cytokines together induce the formation of immunosuppressive TME. Moreover, MITA activation could lead to T cell exhaustion in a manner independently of IFN, which also contributes to the maintenance of immunosuppressive TME. MITA may also promote tumor metastasis via PD-L1 upregulation and autophagy process. In addition, tumors can directly transfer the cGAMP to neighboring cells such as astrocytes by gap junctions, ultimately accelerating the progression of tumor metastasis.