The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS), a critical factor in the innate immune response pathway, is essential for checkpoint blockade immunotherapy in animal models (Wang et al., 2017). Upon binding cytosolic DNA, cGAS synthesizes the second messenger molecule cyclic GMP-AMP (cGAMP), which in turn binds and activates the ...

2024年4月9日 · The cGAS-STING DNA-sensing pathway has emerged as a central mediator of host defense, a cause of numerous human immune diseases, a contributor to fundamental pathological processes of senescence and aging, and a new avenue for triggering inflammation in tumors to improve anti-cancer immunity.

2021年1月11日 · While neoantigens result from the hypermutable nature of dMMR, it is unknown how dMMR activates the cGAS-STING pathway. We show here that loss of the MutLα subunit MLH1, whose defect is responsible for ~50% of dMMR cancers, results in loss of MutLα-specific regulation of exonuclease 1 (Exo1) during DNA repair.

2020年12月19日 · MLH1 Deficiency-Triggered DNA Hyperexcision by Exonuclease 1 Activates the cGAS-STING Pathway. 研究团队发现错配修复缺陷 （dMMR） 肿瘤因为缺失MLH1基因从而促使核酸外切酶ExoI介导产生了胞质DNA，激活肿瘤细胞自身的cGAS-STING通路，增强了T细胞的肿瘤浸润，从而有助于PD-1抗体的抗肿瘤效果；而受损的cGAS-STING通路会导致免疫治疗的不响应。 这个发现为以PD-1抗体为基础的肿瘤治疗提供了新的生物标注物，并为解决那些因为T …

2021年1月11日 · To determine whether dMMR-mediated immunotherapy responsiveness occurs via activation of the cGAS-STING pathway, we generated Mlh1-knockout (Mlh1 −/−) and Mlh1-rescued mouse 4T1 tumor cells, and analyzed the resulting cells for DNA breaks and cytosolic DNA accumulation, events required for cGAS activation (Ablasser and Chen, 2019; Li and ...

MLH1 deficiency triggers activation of the cGAS-STING pathway. Indeed, we have recently shown that tumor cells defective in MLH1 accumulate cytosolic DNA to activate the cGAS-STING pathway, which sensitizes MLH1-deficient tumors to immunotherapy by promoting the priming and infiltration of anti-tumor CD8+ T cells. Impairing the DNA sensing ...

2021年1月11日 · Using tumor models defective in the MMR gene Mlh1 (dMLH1), we show that dMLH1 tumor cells accumulate cytosolic DNA and produce IFN-β in a cGAS-STING-dependent manner, which renders dMLH1 tumors slowly progressive and …

2023年6月2日 · Here, our study reports that methionine deprivation enhances cGAS activity by blocking its methylation, which is catalyzed by methyltransferase SUV39H1. We further show that methylation enhances the chromatin sequestration of cGAS in a UHRF1-dependent manner.

在这篇综述中，作者探讨了cGAS的病理和保护功能，并总结了两个最新的进展，提供了对cGAS-STING通路调控的意外见解。 第一个是关于cGAS与染色质紧密连接的新见解，挑战了“细胞质DNA传感”的概念。 第二个是关于cGAMP作为免疫信号分子的新见解，可以跨细胞传递信号。 这些发现对于治疗免疫病理和改善抗癌免疫具有重要意义。 此外，文章还探讨了cGAS途径在识别自身DNA损伤方面的作用，以及在肿瘤免疫和细胞衰老等方面的应用前景。 cGAS的分布. 自发 …

突变亨廷顿蛋白诱导 MLH1 降解、DNA 过度切除和 cGAS-STING 依赖性细胞凋亡 Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4) Pub Date : 2024-03-18, DOI: 10.1073/pnas.2313652121