Cgas-flox Mouse

cGAS, short for cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase, is a key intracellular DNA sensor. It plays a crucial role in detecting DNA and generating cGAMP, a second messenger. This subsequently triggers the activation of 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. The cGAS-STING pathway is of great biological importance as it is involved in various biological processes and diseases [1].

In the context of diseases, in liver fibrosis models, the upregulation of the cGAS-STING signaling exacerbated liver fibrosis and intrahepatic inflammation, also exacerbating liver sinusoidal endothelial cell (LSEC) impairment and increasing hepatic sinusoidal microthrombosis [5]. In pulmonary fibrosis, aberrant activation of cGAS-STING contributes to fibrotic lung diseases, highlighting its potential as a therapeutic target [1]. In atherosclerosis, IQGAP1 promotes mitochondrial damage, leading to the release of mtDNA which activates the cGAS-STING pathway, inducing endothelial cell pyroptosis [4]. DNAJA2 deficiency activates the cGAS-STING pathway via induction of aberrant mitosis and chromosome instability, suggesting DNAJA2 as a potential target to enhance cancer immunotherapy [2]. Also, liposomes with an optimized ratio of indocyanine green and doxorubicin plus ultrasound can promote oxidized tumor mitochondrial DNA transfer to antigen-presenting cells, effectively activating cGAS-STING signaling for antitumor immunity [3]. In Trypanosoma cruzi infection, host cGAS-STING senses the infection, enhancing parasite growth at the site of entry and contributing to acute-phase parasite restriction in the heart [6]. Phospholipase D3-defective cells show mtDNA build-up in lysosomes, leakage of mtDNA to the cytosol activates cGAS-STING signaling, which upregulates autophagy and affects amyloid precursor C-terminal fragment (APP-CTF) and cholesterol accumulation [7].

In conclusion, cGAS is a vital component of the cGAS-STING pathway, which has far-reaching implications in multiple disease areas such as fibrosis, atherosclerosis, cancer, and infections. The study of cGAS using gene knockout or conditional knockout mouse models has provided significant insights into its role in these diseases, highlighting its potential as a therapeutic target.