Journal
CELL CHEMICAL BIOLOGY
Volume 23, Issue 12, Pages 1539-1549Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2016.10.014
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Funding
- NIH [DP2 OD008677, R01 AI113041, T32 GM066698]
- Cancer Research Coordinating Committee (CRCC)
- Aduro Biotech
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In mammalian cells, the second messenger (2'-5',3'-5') cyclic guanosine monophosphate-adenosine monophosphate (2',3'-cGAMP), is produced by the cytosolic DNA sensor cGAMP synthase (cGAS), and subsequently bound by the stimulator of interferon genes (STING) to trigger interferon response. Thus, the cGAS-cGAMP-STING pathway plays a critical role in pathogen detection, as well as pathophysiological conditions including cancer and autoimmune disorders. However, studying and targeting this immune signaling pathway has been challenging due to the absence of tools for high-throughput analysis. We have engineered an RNA-based fluorescent biosensor that responds to 2',3'-cGAMP. The resulting mix-and-go'' cGAS activity assay shows excellent statistical reliability as a high-throughput screening (HTS) assay and distinguishes between direct and indirect cGAS inhibitors. Furthermore, the biosensor enables quantitation of 2',3'-cGAMP in mammalian cell lysates. We envision this biosensorbased assay as a resource to study the cGAScGAMP- STING pathway in the context of infectious diseases, cancer immunotherapy, and autoimmune diseases.
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