A novel virus-induced cyclic dinucleotide, 2'3'-c-di-GMP, mediates STING-dependent antiviral immunity in Drosophila

Cai, H.; Li, L.; Slavik, K.; Huang, J.; Yin, T.; Hedelin, L.; Xiang, Z.; Yang, Y.; Li, X.; Chen, Y.; Wei, Z.; Deng, H.; Chen, D.; Jiao, R.; Martins, N.; Meignin, C.; Kranzusch, P. J.; Imler, J.-L.

doi:10.1101/2023.05.08.539652

bioRxiv · 10.1101/2023.05.08.539652

A novel virus-induced cyclic dinucleotide, 2'3'-c-di-GMP, mediates STING-dependent antiviral immunity in Drosophila

Cai, H.·Li, L.·Slavik, K.·Huang, J.·Yin, T.·Hedelin, L.·Xiang, Z.·Yang, Y.·Li, X.·Chen, Y.·Wei, Z.·Deng, H.·Chen, D.·Jiao, R.·Martins, N.·Meignin, C.·Kranzusch, P. J.·Imler, J.-L.

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Abstract

In mammals, the enzyme cGAS senses the presence of cytosolic DNA and synthesizes the cyclic dinucleotide (CDN) 2'3'-cGAMP. This CDN binds to and activates the protein STING to trigger immunity. We recently discovered in the model organism Drosophila melanogaster two cGAS-like receptors (cGLRs) that activate STING-dependent antiviral immunity and can produce 3'2'-cGAMP, in addition to 2'3'-cGAMP. Here we explore CDN-mediated immunity in 14 different Drosophila species covering 50 million years of evolution and report that 2'3'-cGAMP and 3'2'-cGAMP fail to control infection by Drosophila C virus in D. serrata, D. sechellia and D. mojavensis. Using an accurate and sensitive mass spectrometry method, we discover an unexpected diversity of CDNs produced in a cGLR-dependent manner in response to viral infection in D. melanogaster, including a novel CDN, 2'3'-c-di-GMP. We show that 2'3'-c-di-GMP is the most potent STING agonist identified so far in D. melanogaster and that this molecule also activates a strong antiviral transcriptional response in D. serrata. Our results shed light on the evolution of cGLRs in flies and provide a basis for the understanding of the function and regulation of this emerging family of PRRs in animal innate immunity.

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Cai, H., Li, L., Slavik, K., Huang, J., Yin, T., Hedelin, L., Xiang, Z., Yang, Y., Li, X., Chen, Y., Wei, Z., Deng, H., Chen, D., Jiao, R., Martins, N., Meignin, C., Kranzusch, P. J., Imler, J.-L.. 2023-05-09. A novel virus-induced cyclic dinucleotide, 2'3'-c-di-GMP, mediates STING-dependent antiviral immunity in Drosophila. https://doi.org/10.1101/2023.05.08.539652

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