基于结构的 2'3'-cGAMP 细胞间转运机制在 cGAS-STING 免疫途径中的作用。
Structure-based mechanisms of 2'3'-cGAMP intercellular transport in the cGAS-STING immune pathway.
机构信息
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 311027, China; Department of Infectious Diseases, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China.
Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
出版信息
Trends Immunol. 2023 Jun;44(6):450-467. doi: 10.1016/j.it.2023.04.006. Epub 2023 May 4.
Upon activation by double-stranded DNA (dsDNA), the cytosolic dsDNA sensor cyclic GMP-AMP synthase (cGAS) synthesizes the diffusible cyclic dinucleotide 2'3'-cGAMP (cyclic GMP-AMP), which subsequently binds to the adaptor STING, triggering a cascade of events leading to an inflammatory response. Recent studies have highlighted the role of 2'3'-cGAMP as an 'immunotransmitter' between cells, a process facilitated by gap junctions as well as by specialized membrane-spanning importer and exporter channels. This review highlights recent advances from a structural perspective of intercellular trafficking of 2'3'-cGAMP, with particular emphasis on the binding of importer SLC19A1 to 2'3'-cGAMP, as well as the significance of associated folate nutrients and antifolate therapeutics. This provides a path forward for structure-guided understanding of the transport cycle in immunology, as well as for candidate targeting approaches towards therapeutic intervention in inflammation.
双链 DNA（dsDNA）激活后，细胞质 dsDNA 传感器环鸟苷酸-腺苷酸合酶（cGAS）合成可扩散的环二核苷酸 2'3'-cGAMP（环鸟苷酸-腺苷酸），随后与衔接蛋白 STING 结合，引发一系列导致炎症反应的事件。最近的研究强调了 2'3'-cGAMP 作为细胞间“免疫递质”的作用，这一过程由间隙连接以及专门的跨膜导入和导出通道促进。本综述从细胞间 2'3'-cGAMP 运输的结构角度强调了最近的进展，特别强调了导入器 SLC19A1 与 2'3'-cGAMP 的结合，以及相关叶酸营养物和抗叶酸治疗药物的意义。这为基于结构的免疫学运输周期理解以及炎症治疗的候选靶向方法提供了前进的道路。
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