Structural insights into the regulation, ligand recognition, and oligomerization of bacterial STING

Mei-Hui Hou, Yu-Chuan Wang, Chia-Shin Yang, Kuei-Fen Liao, Je-Wei Chang, Orion Shih, Yi-Qi Yeh, Manoj Kumar Sriramoju, Tzu-Wen Weng, U-Ser Jeng, Shang-Te Danny Hsu and Yeh Chen ()
Additional contact information
Mei-Hui Hou: Genomics BioSci. & Tech. Co. Ltd.
Yu-Chuan Wang: Genomics BioSci. & Tech. Co. Ltd.
Chia-Shin Yang: Genomics BioSci. & Tech. Co. Ltd.
Kuei-Fen Liao: Hsinchu Science Park
Je-Wei Chang: Hsinchu Science Park
Orion Shih: Hsinchu Science Park
Yi-Qi Yeh: Hsinchu Science Park
Manoj Kumar Sriramoju: Academia Sinica
Tzu-Wen Weng: Academia Sinica
U-Ser Jeng: Hsinchu Science Park
Shang-Te Danny Hsu: Academia Sinica
Yeh Chen: National Chung Hsing University

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-44052-x

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