cGAS, also known as cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase, is a central cytoplasmic DNA sensor. Its essential function is to detect DNA and generate cGAMP, a second messenger. cGAMP then triggers the activation of stimulator of interferon genes (STING), initiating a signaling cascade that leads to the stimulation of type I interferons and other signaling molecules involved in immune responses. This pathway is crucial in various biological processes, especially in innate immunity [1,5].

Aberrant activation of cGAS-STING contributes to fibrotic lung diseases. In a model of pulmonary fibrosis, targeting the cGAS-STING pathway, such as using inhibitors of cGAS and STING, shows potential therapeutic implications [1]. In DNAJA2-deficient tumor cells, the cGAS-STING pathway is activated due to aberrant mitosis and chromosome instability, enhancing the response to immune-checkpoint blockade (ICB) therapy [2]. In atherosclerosis models, IQGAP1 promotes mitochondrial damage, leading to mtDNA release and activation of the cGAS-STING pathway, which in turn induces endothelial cell pyroptosis. Small-molecule inhibitors of cGAS or STING can reverse this effect [3]. In liver fibrosis models, activation of the cGAS-STING signaling pathway promotes liver fibrosis and hepatic sinusoidal microthrombosis [4]. In Trypanosoma cruzi infection models, cGAS-STING senses the infection, enhancing parasite growth at the site of entry and contributing to acute-phase parasite restriction in the heart [6]. In PLD3-defective cells, lysosomal leakage of mtDNA activates the cGAS-STING signaling, which upregulates autophagy and induces amyloid precursor C-terminal fragment (APP-CTF) and cholesterol accumulation. STING inhibition normalizes APP-CTF levels [7].

In conclusion, cGAS plays a vital role in innate immune responses by detecting DNA and activating the cGAS-STING pathway. Through gene knockout or conditional knockout mouse models and other loss-of-function experiments, research has revealed its significant impact on various disease conditions, including pulmonary fibrosis, cancer, atherosclerosis, liver fibrosis, parasitic infection, and Alzheimer-related processes. Understanding cGAS function in these models provides insights into disease mechanisms and potential therapeutic targets.

References:

1. Zhang, Jing, Zhang, Lanlan, Chen, Yutian, Li, Bo, Mo, Chunheng. 2023. The role of cGAS-STING signaling in pulmonary fibrosis and its therapeutic potential. In Frontiers in immunology, 14, 1273248. doi:10.3389/fimmu.2023.1273248. https://pubmed.ncbi.nlm.nih.gov/37965345/

2. Huang, Yaping, Lu, Changzheng, Wang, Hanzhi, Fu, Yang-Xin, Li, Guo-Min. 2023. DNAJA2 deficiency activates cGAS-STING pathway via the induction of aberrant mitosis and chromosome instability. In Nature communications, 14, 5246. doi:10.1038/s41467-023-40952-0. https://pubmed.ncbi.nlm.nih.gov/37640708/

3. An, Cheng, Sun, Fei, Liu, Can, Zhang, Chengxin, Ge, Shenglin. 2023. IQGAP1 promotes mitochondrial damage and activation of the mtDNA sensor cGAS-STING pathway to induce endothelial cell pyroptosis leading to atherosclerosis. In International immunopharmacology, 123, 110795. doi:10.1016/j.intimp.2023.110795. https://pubmed.ncbi.nlm.nih.gov/37597406/

4. Luo, Shaobin, Luo, Rongkun, Lu, Huanyuan, Huang, Feizhou, Lei, Zhao. 2023. Activation of cGAS-STING signaling pathway promotes liver fibrosis and hepatic sinusoidal microthrombosis. In International immunopharmacology, 125, 111132. doi:10.1016/j.intimp.2023.111132. https://pubmed.ncbi.nlm.nih.gov/37951190/

5. Jin, Ximing, Wang, Wenjia, Zhao, Xinwei, Chen, Zhuo, Huang, Cong. 2023. The battle between the innate immune cGAS-STING signaling pathway and human herpesvirus infection. In Frontiers in immunology, 14, 1235590. doi:10.3389/fimmu.2023.1235590. https://pubmed.ncbi.nlm.nih.gov/37600809/

6. Perumal, Natasha, White, Brooke, Sanchez-Valdez, Fernando, Tarleton, Rick L. . cGAS-STING Pathway Activation during Trypanosoma cruzi Infection Leads to Tissue-Dependent Parasite Control. In Journal of immunology (Baltimore, Md. : 1950), 211, 1123-1133. doi:10.4049/jimmunol.2300373. https://pubmed.ncbi.nlm.nih.gov/37603014/

7. Van Acker, Zoë P, Perdok, Anika, Hellemans, Ruben, Damme, Markus, Annaert, Wim. 2023. Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism. In Nature communications, 14, 2847. doi:10.1038/s41467-023-38501-w. https://pubmed.ncbi.nlm.nih.gov/37225734/