cGAS, also known as cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase, is a crucial intracellular DNA sensor. Its main function is to detect DNA and generate cGAMP, a second messenger. cGAMP then activates the stimulator of interferon genes (STING), initiating a signaling cascade that leads to the stimulation of type I interferons and other molecules involved in immune responses. This pathway is of great biological importance as it is involved in various immune-related processes and disease developments [1].

In various disease conditions, studies have revealed the role of cGAS-STING pathway. In pulmonary fibrosis, its aberrant activation contributes to the disease, suggesting potential therapeutic implications by targeting this pathway [1]. In cancer, DNAJA2 deficiency activates the cGAS-STING pathway via aberrant mitosis, enhancing immune-checkpoint blockade therapy response [2]. In atherosclerosis, IQGAP1 promotes mitochondrial damage, releasing mtDNA to activate cGAS-STING and leading to endothelial cell pyroptosis [3]. In liver fibrosis, activation of the cGAS-STING signaling pathway exacerbates the condition and hepatic sinusoidal microthrombosis [4]. In human herpesvirus infections, the cGAS-STING pathway is involved in the host-virus battle, with the virus evading immunity by acting on this pathway [5]. In Trypanosoma cruzi infection, cGAS-STING activation leads to tissue-dependent parasite control [6]. In Alzheimer's disease-related research, PLD3-defective cells show mtDNA build-up, activating cGAS-STING and affecting APP metabolism [7].

In conclusion, cGAS is a key sensor in the cGAS-STING signaling pathway, playing significant roles in immune responses and disease development. Studies using gene knockout or conditional knockout mouse models, though not always explicitly detailed in these abstracts, likely contribute to understanding its functions in diseases such as pulmonary fibrosis, cancer, atherosclerosis, liver fibrosis, herpesvirus infections, Trypanosoma cruzi infection, and Alzheimer's-related processes. This knowledge helps in exploring potential therapeutic strategies targeting the cGAS-STING pathway for these diseases.

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/