Novel regulatory mechanisms and agonists of STING

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Abstract The innate immunity is the first line of defense of our body against invading pathogens such as viruses and bacteria. The cGAS/STING pathway is a recently discovered innate immunity pathway that plays critical roles in eliminating cytosolic DNA virus. Viral DNA in the cytosol is detected by the DNA sensor cyclic-GMP-AMP synthase (cGAS), which becomes active and synthesizes the second messenger cyclic-GMP-AMP (cGAMP) using ATP and GTP as the substrates. cGAMP binds and activates adaptor protein Stimulator of Interferon Genes (STING), a transmembrane protein normally residing on the endoplasmic reticulon (ER) membrane. cGAMP-bound STING polymerizes and translocates to the Golgi apparatus, where it activates the downstream signaling proteins the TBK1 kinase and the transcription factor IRF3. This signaling pathway ultimately leads to a plethora of anti-viral responses, including the production of interferons, induction of inflammatory responses and autophagy. The cGAS/STING can also launch immune responses to self-DNA, such as damaged DNA leaked into the cytosol in cancer cells. In fact, mounting evidence in the past few years have demonstrated the cGAS/STING pathway plays a critical role in immune responses to cancer through several mechanisms. cGAS/STING signaling can boost the effects of immune checkpoint inhibitors such as anti-PD1 and anti-PD-L1 antibodies in cancer therapy, whereas loss of function of the cGAS/STING pathway leads to severe immuno- deficiency and impaired response to immune checkpoint inhibitors. STING therefore has become a major target for cancer therapy in recent years, with several agonists undergoing clinic trials at present. One major goal of this project is to advance our understanding of the fundamental regulatory mechanisms of STING by using cryo-EM structural analyses in combination with biophysical and cell-based functional assays. In addition, our preliminary data revealed a novel cryptic agonist binding site in STING, opening the door to the development of a completely new class of STING agonists. The second major direction of the project is therefore to further characterize this new binding site in STING, and design more potent and specific agonists based on the structures. New STING agonists will be synthesized and tested in biophysical and functional assays, and structurally characterized using cryo-EM. The new agonists could be used as chemical tools for further mechanistic studies, and may be developed into anti-cancer drugs in future.