Genomics BioSci. & Tech. Co. Ltd., New Taipei, 221411, Taiwan.
National Synchrotron Radiation Research Center, Hsinchu Science Park, Hsinchu, 300092, Taiwan.
Nat Commun. 2023 Dec 21;14(1):8519. doi: 10.1038/s41467-023-44052-x.
The cyclic GMP-AMP synthase (cGAS)/stimulator of interferon gene (STING) signaling pathway plays a critical protective role against viral infections. Metazoan STING undergoes multilayers of regulation to ensure specific signal transduction. However, the mechanisms underlying the regulation of bacterial STING remain unclear. In this study, we determined the crystal structure of anti-parallel dimeric form of bacterial STING, which keeps itself in an inactive state by preventing cyclic dinucleotides access. Conformational transition between inactive and active states of bacterial STINGs provides an on-off switch for downstream signaling. Some bacterial STINGs living in extreme environment contain an insertion sequence, which we show codes for an additional long lid that covers the ligand-binding pocket. This lid helps regulate anti-phage activities. Furthermore, bacterial STING can bind cyclic di-AMP in a triangle-shaped conformation via a more compact ligand-binding pocket, forming spiral-shaped protofibrils and higher-order fibril filaments. Based on the differences between cyclic-dinucleotide recognition, oligomerization, and downstream activation of different bacterial STINGs, we proposed a model to explain structure-function evolution of bacterial STINGs.
环鸟苷酸-腺苷酸合成酶（cGAS）/干扰素基因刺激物（STING）信号通路在抵抗病毒感染中起着至关重要的保护作用。后生动物 STING 经历了多层次的调节，以确保特定的信号转导。然而，细菌 STING 的调节机制尚不清楚。在这项研究中，我们确定了细菌 STING 反平行二聚体形式的晶体结构，该结构通过阻止环二核苷酸进入来保持自身处于非活性状态。细菌 STING 的无活性和活性状态之间的构象转变为下游信号提供了开/关开关。一些生活在极端环境中的细菌 STING 含有一个插入序列，我们证明该序列编码了一个额外的长盖，覆盖配体结合口袋。该盖子有助于调节抗噬菌体活性。此外，细菌 STING 可以通过更紧凑的配体结合口袋以三角形构象结合环二腺苷酸，形成螺旋形原纤维和更高阶的纤维丝。基于不同细菌 STING 对环二核苷酸的识别、寡聚化和下游激活的差异，我们提出了一个模型来解释细菌 STING 的结构-功能进化。
