哺乳动物先天免疫系统使用环状GMP-AMP合酶（cGAS）在抗病毒和抗肿瘤免疫反应中合成环状二核苷酸2'，3'-cGAMP。 2'，3'-cGAMP是一种核苷酸第二信使，通过结合并激活干扰素基因刺激体（STING）受体来启动炎症信号传导。细菌还编码cGAS / DncV样核苷酸转移酶（CD-NT酶），以产生核苷酸第二信使来启动抗病毒（抗噬菌体）信号。细菌CD-NT酶产生广泛的环状寡核苷酸，但尚未记录到产生2',3'-cGAMP。在本研究中，我们发现细菌CD-NT酶能产生2',3'-cGAMP来限制噬菌体复制。细菌2',3'-cGAMP与CD-NT酶相关蛋白14（Cap14），一种未知功能的跨膜蛋白结合。利用电生理学，我们展示了Cap14是一种选择性氯离子通道，可以通过2',3'-cGAMP的结合来激活。Cap14采用模块化结构，具有N端跨膜结构域和C端核苷酸结合的SAVED结构域。域交换实验证明，Cap14跨膜区域可以被核酸酶代替，从而生成对2',3'-cGAMP选择性的生物传感器。本研究揭示了2',3'-cGAMP信号传导在元生动物以外的细菌中存在。此外，我们的发现表明，细菌免疫途径中未知功能的跨膜蛋白可能广泛作为核苷酸门控离子通道发挥作用。

The mammalian innate immune system uses cyclic GMP-AMP synthase (cGAS) to synthesize the cyclic dinucleotide 2',3'-cGAMP during antiviral and antitumor immune responses. 2',3'-cGAMP is a nucleotide second messenger that initiates inflammatory signaling by binding to and activating the stimulator of interferon genes (STING) receptor. Bacteria also encode cGAS/DncV-like nucleotidyltransferases (CD-NTases) that produce nucleotide second messengers to initiate antiviral (antiphage) signaling. Bacterial CD-NTases produce a wide range of cyclic oligonucleotides but have not been documented to produce 2',3'-cGAMP. Here we discovered bacterial CD-NTases that produce 2',3'-cGAMP to restrict phage replication. Bacterial 2',3'-cGAMP binds to CD-NTase associated protein 14 (Cap14), a transmembrane protein of unknown function. Using electrophysiology, we show that Cap14 is a chloride-selective ion channel that is activated by 2',3'-cGAMP binding. Cap14 adopts a modular architecture, with an N-terminal transmembrane domain and a C-terminal nucleotide-binding SAVED domain. Domain-swapping experiments demonstrated the Cap14 transmembrane region could be substituted with a nuclease, thereby generating a biosensor that is selective for 2',3'-cGAMP. This study reveals that 2',3'-cGAMP signaling extends beyond metazoa to bacteria. Further, our findings suggest that transmembrane proteins of unknown function in bacterial immune pathways may broadly function as nucleotide-gated ion channels.