cGAS, short for cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase, is a key intracellular DNA sensor. Its primary 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 cGAS-STING pathway is of great biological importance in innate immunity and has implications in various disease processes [1,5].

In multiple disease conditions, the cGAS-STING pathway has been implicated. In pulmonary fibrosis, aberrant activation of cGAS-STING contributes to the disease, suggesting potential therapeutic implications by targeting this pathway [1]. In liver fibrosis, activation of the cGAS-STING signaling pathway promotes fibrosis and hepatic sinusoidal microthrombosis [4]. In atherosclerosis, IQGAP1 promotes mitochondrial damage, leading to the activation of the cGAS-STING pathway, which induces endothelial cell pyroptosis [3]. Also, DNAJA2 deficiency activates the cGAS-STING pathway via aberrant mitosis, enhancing immune-checkpoint blockade therapy response in tumors [2]. In the context of infections, human herpesvirus can trigger cGAS activation, while the virus tries to evade host immunity by acting on this pathway [5]. In Trypanosoma cruzi infection, cGAS-STING sensing impacts parasite growth in a tissue-dependent manner [6]. Moreover, in cells defective in Phospholipase D3, lysosomal leakage of mtDNA activates cGAS-STING signaling, which affects APP metabolism [7].

In conclusion, cGAS is a crucial component in the cGAS-STING pathway, playing a significant role in innate immune responses. Studies, especially those using gene knockout or conditional knockout mouse models, have revealed its importance in various disease areas such as fibrosis, atherosclerosis, cancer, and infectious diseases. Understanding cGAS function through 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/