The Cyclopeptide Astin C Specifically Inhibits the Innate Immune CDN Sensor STING.

Summary cGAS-STING signaling is essential for innate immunity. Its misregulation promotes cancer or autoimmune and autoinflammatory diseases, and it is imperative to identify effective lead compounds that specifically downregulate the pathway. We report here that astin C, a cyclopeptide isolated from the medicinal plant Aster tataricus , inhibits cGAS-STING signaling and the innate inflammatory responses triggered by cytosolic DNAs. Moreover, mice treated with astin C are more susceptible to HSV-1 infection. Consistently, astin C markedly attenuates the autoinflammatory responses in Trex1 ^−/− BMDM cells and in Trex1 ^−/− mouse autoimmune disease model. Mechanistically, astin C specifically blocks the recruitment of IRF3 onto the STING signalosome. Collectively, this study characterizes a STING-specific small-molecular inhibitor that may be applied for potentially manipulating the STING-mediated clinical diseases. Graphical Abstract Highlights • Astin C impairs cGAS-STING signaling and the inflammatory responses • Astin C attenuates autoinflammatory responses in Trex1 ^−/− cells and disease model • Astin C specifically binds to STING • Astin C prevents the recruitment of IRF3 onto STING signalosome Li et al. have characterized a small-molecule cyclopeptide, astin C, which specifically inhibits cGAS-STING signaling as well as the innate inflammatory responses. This finding provides a way to potentially manipulate STING-mediated clinical diseases. [ABSTRACT FROM AUTHOR]