Cyclic GMP-AMP synthase (cGAS) is a key sensor responsible for cytosolic DNA detection. Here we report that GTPase-activating protein SH3 domain–binding protein 1 (G3BP1) is critical for DNA sensing and efficient activation of cGAS. G3BP1 enhanced DNA binding of cGAS by promoting the formation of large cGAS complexes. G3BP1 deficiency led to inefficient DNA binding by cGAS and inhibited cGAS-dependent interferon (IFN) production. The G3BP1 inhibitor epigallocatechin gallate (EGCG) disrupted existing G3BP1–cGAS complexes and inhibited DNA-triggered cGAS activation, thereby blocking DNA-induced IFN production both in vivo and in vitro. EGCG administration blunted self DNA–induced autoinflammatory responses in an Aicardi–Goutières syndrome (AGS) mouse model and reduced IFN-stimulated gene expression in cells from a patient with AGS. Thus, our study reveals that G3BP1 physically interacts with and primes cGAS for efficient activation. Furthermore, EGCG-mediated inhibition of G3BP1 provides a potential treatment for cGAS-related autoimmune diseases.
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The MS-identified cGAS-interacting protein list is provided in Supplementary Tables 1 and 2. The primer sequences used for qPCR are provided in Supplementary Table 3. The information on antibodies used in our study is provided in Supplementary Table 4. We also provide full scans of all the blots and gels as Supplementary Dataset 1. The data that support the findings of this study are available from the corresponding authors upon reasonable request.
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We sincerely thank the patient with AGS and his sibling for donating PBMCs. We thank J. Tazi (Université Montpellier 2) for providing the G3bp1+/– mice, Cancer Research Technology Limited for providing the Trex1+/– mice, C. Widmann (University of Lausanne) for providing HA-G3BP1 plasmid, J. W. Chin (Cambridge) for providing pCDF PylT-1 plasmid, J. U. Jung (University of Southern California) for providing cGAS cDNA construct, H. Shu (Wuhan University) for providing STING cDNA construct, J. Han (Xiamen University) for providing HSV-1, M. Yang (Tsinghua University) for help with protein purification. We thank H. Yu (UT Southwestern Medical Center), Y. Zheng (Carnegie Institution for Science) and H. Qi (Tsinghua University) for helpful discussion and critical reading of the manuscript. This work was supported by grants from the China National Natural Science Foundation (No. 81771708 to T.L., No. 81521064 to X.-M.Z.).
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Nature Immunology (2019)