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PreprintCited by 66interferon and immune responsesInvertebrate Immune Response MechanismsImmune Response and Inflammation

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

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Cai, Hua, Li, Lihua, Slavik, Kailey, Huang, Jingxian, Yin, Ting, Hédelin, Léna, Xiang, Zhangmin, Yang, Yunyun, Li, Xiaoyan, Chen, Yuqiang, Wei, Ziming, Deng, Huimin, Chen, Di, Jiao, Renjie, Martins, Nelson, Meignin, Carine, Kranzusch, Philip, Imler, Jean-Luc·2023·Immunity
DOI 10.1101/2023.05.08.539652PMC PMC11781366

Preprint — published as 10.1016/j.immuni.2023.08.006

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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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Metadata

Authors
Cai, H., Li, L., Slavik, K., Huang, J., Yin, T., Hédelin, L., Xiang, Z., Yang, Y., Li, X., Chen, Y., Wei, Z., Deng, H., Chen, D., Jiao, R., Martins, N., Meignin, C., Kranzusch, P., & Imler, J.-L.
Affiliations
  • Guangzhou Medical University (CN)
  • Harvard University (US)
  • Centre National de la Recherche Scientifique (FR)
  • Guangdong Academy of Sciences (CN)
Corresponding author
  • Cai, Hua
  • Kranzusch, Philip
ORCID
Venue
Immunity
Publisher
openRxiv
Published
2023-05-09
Volume
56
Issue
9
Pages
1991-2005.e9
ISSN
1074-7613 (ISSN-L)
DOI
10.1101/2023.05.08.539652
PMC
PMC11781366
OpenAlex
W4386378511
Cited by
66
References
1
Citations by year
2026: 16 · 2025: 20 · 2024: 25 · 2023: 5
FWCI
7.23
Type
journal article
Language
en
Open access
Locations
  • Immunity (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion, other-oa)
  • PubMed Central (submittedVersion)
Funders
  • Cancer Research Institute
  • Parker Institute for Cancer Immunotherapy
  • Mark Foundation For Cancer Research
  • Agence Nationale de la Recherche (ANR-10-IDEX-0002, ANR-22-CE15-0019, ANR-17-EURE-, ANR-20-SFRI-0012, ANR-17-EURE-0023, ANR-10-IDEX, ANR-11-EQPX-0022, ANR-17, ANR-10)
  • National Natural Science Foundation of China (31970538, 32200578, 32000662, 2020YFA0803202, 2017BT01S155)
  • Centre National de la Recherche Scientifique (ANR-11-EQPX-0022, ANR-10-IDEX-0002)
  • National Institutes of Health (1dp2gm146250-01)
  • National Cancer Institute (F99CA274660)
  • National Institute of General Medical Sciences (DP2 GM146250)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Life Sciences › Immunology and Microbiology › Immunology › Invertebrate Immune Response Mechanisms
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
cyclic dinucleotides, cGAMP, STING, antiviral immunity, Drosophila melanogaster, Drosophila serrata, Drosophila C virus, innate immunity, pattern recognition receptors, cytosolic DNA sensing

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