Role of the cGAS-STING pathway in systemic and organ-specific diseases.
Role of the cGAS-STING pathway in systemic and organ-specific diseases.
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cGAS-STING通路在系统性和器官特异性疾病中的作用
DOI：
10.1038/s41581-022-00589-6
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发表时间：
2022-09
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影响因子：
--
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细胞配备了许多识别核酸的传感器，这可能是为了防御病毒而进化的。一旦被触发，这些传感器就会刺激I型干扰素和其他细胞因子的产生，这些细胞因子可以激活免疫细胞并促进抗病毒状态。进化保守酶环GMP-AMP合成酶（cGAS）是最近发现的DNA传感器之一。配体结合后，cGAS二聚合成二核苷酸第二信使2′，3′-环GMP-AMP (cGAMP)，其高亲和力结合干扰素基因内质网蛋白刺激因子（STING），从而引发炎症反应。结合cgas的DNA不受序列限制，长度必须只有45个核苷酸；因此，cGAS也可以被自身基因组或线粒体DNA刺激。这种广泛的特异性可能解释了为什么cGAS-STING通路与许多自身炎症、自身免疫和神经退行性疾病有关；该途径在急性和慢性肾损伤时也可能被激活。利用合成环二核苷酸或cGAMP代谢抑制剂对cGAS-STING通路进行治疗性操作，有望增强癌症或病毒感染的免疫反应。相比之下，cGAS或STING抑制剂可能对这种促炎途径长期激活的疾病有用。环GMP-AMP合成酶(cGAS) -干扰素基因刺激因子（STING）途径不仅参与宿主防御感染，而且可导致免疫失调。在这里，作者研究了cGAS-STING的生物学和生物化学，并讨论了其在疾病中的作用和潜在的靶向治疗方法。环GMP-AMP合成酶（cGAS）是一种进化保守的细胞质核酸传感器，它合成环二核苷酸第二信使2 ',3 ' -环GMP-AMP (cGAMP)，其参与干扰素基因刺激因子（STING）触发炎症细胞因子的产生，包括I型干扰素。胞外cGAMP被跨膜和可溶性外核苷酸焦磷酸酶/磷酸二酯酶1水解，并通过cGAMP入口进入邻近细胞。转移到邻近和远处的细胞使cGAMP作为免疫递质，调节抗病毒反应、抗肿瘤免疫和肿瘤转移。基因组或线粒体自身DNA激活cGAS-STING与许多自身炎症、自身免疫和神经退行性疾病、细胞衰老和衰老以及急性和慢性肾损伤有关。微生物组可以通过cGAS感应共生DNA、微生物诱导的内源性逆转录病毒或因感染诱导的细胞损伤而释放的自身DNA来刺激或抑制cGAS - sting。这些相互作用会影响肠道和皮肤的稳态。通过调节参与cGAS-STING通路及其调节因子激活的蛋白，可为减轻或增强cGAS-STING驱动的炎症反应提供治疗机会。
Cells are equipped with numerous sensors that recognize nucleic acids, which probably evolved for defence against viruses. Once triggered, these sensors stimulate the production of type I interferons and other cytokines that activate immune cells and promote an antiviral state. The evolutionary conserved enzyme cyclic GMP–AMP synthase (cGAS) is one of the most recently identified DNA sensors. Upon ligand engagement, cGAS dimerizes and synthesizes the dinucleotide second messenger 2′,3′-cyclic GMP–AMP (cGAMP), which binds to the endoplasmic reticulum protein stimulator of interferon genes (STING) with high affinity, thereby unleashing an inflammatory response. cGAS-binding DNA is not restricted by sequence and must only be >45 nucleotides in length; therefore, cGAS can also be stimulated by self genomic or mitochondrial DNA. This broad specificity probably explains why the cGAS–STING pathway has been implicated in a number of autoinflammatory, autoimmune and neurodegenerative diseases; this pathway might also be activated during acute and chronic kidney injury. Therapeutic manipulation of the cGAS–STING pathway, using synthetic cyclic dinucleotides or inhibitors of cGAMP metabolism, promises to enhance immune responses in cancer or viral infections. By contrast, inhibitors of cGAS or STING might be useful in diseases in which this pro-inflammatory pathway is chronically activated. The cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway not only is involved in host defence against infection but can lead to immune dysregulation. Here, the authors examine the biology and biochemistry of cGAS–STING and discuss its role in disease and potential approaches to therapeutic targeting. Cyclic GMP–AMP synthase (cGAS) is an evolutionarily conserved cytosolic nucleic acid sensor that synthesizes the cyclic dinucleotide second messenger 2′,3′-cyclic GMP–AMP (cGAMP), which engages stimulator of interferon genes (STING) to trigger the production of inflammatory cytokines, including type I interferons. Extracellular cGAMP is hydrolysed by transmembrane and soluble ectonucleotide pyrophosphatase/phosphodiesterase 1, and enters neighbouring cells via cGAMP importers. Transfer to adjoining and distant cells enables cGAMP to act as an immunotransmitter and modulate antiviral responses, antitumour immunity and tumour metastasis. Activation of cGAS–STING by genomic or mitochondrial self DNA has been implicated in numerous autoinflammatory, autoimmune and neurodegenerative diseases, cell senescence and ageing, as well as in acute and chronic kidney injury. The microbiome can stimulate or inhibit cGAS–STING via cGAS sensing of commensal DNA, microorganism-induced endogenous retroviruses, or self DNA released owing to infection-induced cell damage. These interactions can affect gut and skin homeostasis. Modulating the proteins involved in the activation of the cGAS–STING pathway and its regulators provides therapeutic opportunities to attenuate or enhance cGAS–STING-driven inflammatory responses.
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影响因子：
64.5
作者：
Caielli S;Cardenas J;de Jesus AA;Baisch J;Walters L;Blanck JP;Balasubramanian P;Stagnar C;Ohouo M;Hong S;Nassi L;Stewart K;Fuller J;Gu J;Banchereau JF;Wright T;Goldbach-Mansky R;Pascual V
通讯作者：
Pascual V
影响因子：
64.8
作者：
Baker DJ;Childs BG;Durik M;Wijers ME;Sieben CJ;Zhong J;Saltness RA;Jeganathan KB;Verzosa GC;Pezeshki A;Khazaie K;Miller JD;van Deursen JM
通讯作者：
van Deursen JM
影响因子：
8.8
作者：
Ahn J;Son S;Oliveira SC;Barber GN
通讯作者：
Barber GN
DOI：
10.1084/jem.20151876
发表时间：
2016-05-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Caielli S;Athale S;Domic B;Murat E;Chandra M;Banchereau R;Baisch J;Phelps K;Clayton S;Gong M;Wright T;Punaro M;Palucka K;Guiducci C;Banchereau J;Pascual V
通讯作者：
Pascual V
影响因子：
13.3
作者：
An, Jie;Durcan, Laura;Elkon, Keith B.
通讯作者：
Elkon, Keith B.