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

Hua Cai; Lihua Li; Kailey M. Slavik; Jingxian Huang; Ting Yin; Xianlong Ai; Léna Hédelin; Gabrielle Haas; Zhangmin Xiang; Yunyun Yang; Xiaoyan Li; Yuqiang Chen; Ziming Wei; Huimin Deng; Di Chen; Renjie Jiao; Nelson Martins; Carine Meignin; Philip J. Kranzusch; Jean Luc Imler

doi:10.1016/j.immuni.2023.08.006

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

Hua Cai^*, Lihua Li, Kailey M. Slavik, Jingxian Huang, Ting Yin, Xianlong Ai, Léna Hédelin, Gabrielle Haas, Zhangmin Xiang, Yunyun Yang, Xiaoyan Li, Yuqiang Chen, Ziming Wei, Huimin Deng, Di Chen, Renjie Jiao, Nelson Martins, Carine Meignin, Philip J. Kranzusch^*, Jean Luc Imler

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

15 Citations (Scopus)

Abstract

In mammals, the enzyme cGAS senses the presence of cytosolic DNA and synthesizes the cyclic dinucleotide (CDN) 2′3′-cGAMP, which triggers STING-dependent immunity. In Drosophila melanogaster, two cGAS-like receptors (cGLRs) produce 3′2′-cGAMP and 2′3′-cGAMP to activate STING. We explored CDN-mediated immunity in 14 Drosophila species covering 50 million years of evolution and found that 2′3′-cGAMP and 3′2′-cGAMP failed to control infection by Drosophila C virus in D. serrata and two other species. We discovered diverse CDNs produced in a cGLR-dependent manner in response to viral infection in D. melanogaster, including 2′3′-c-di-GMP. This CDN was a more potent STING agonist than cGAMP in D. melanogaster and it also activated a strong antiviral transcriptional response in D. serrata. Our results shed light on the evolution of cGLRs in flies and provide a basis for understanding the function and regulation of this emerging family of pattern recognition receptors in animal innate immunity.

Original language	English
Pages (from-to)	1991-2005.e9
Journal	Immunity
Volume	56
Issue number	9
DOIs	https://doi.org/10.1016/j.immuni.2023.08.006
Publication status	Published - 12 Sept 2023
Externally published	Yes

Keywords

c-di-GMP
cGAMP
cGAS
cGLR
Cyclic dinucleotide
Drosophila
Evolution
Pattern recognition receptor
STING
Virus

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Cai, H., Li, L., Slavik, K. M., Huang, J., Yin, T., Ai, X., Hédelin, L., Haas, G., 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). The virus-induced cyclic dinucleotide 2′3′-c-di-GMP mediates STING-dependent antiviral immunity in Drosophila. Immunity, 56(9), 1991-2005.e9. https://doi.org/10.1016/j.immuni.2023.08.006

@article{8d2955ddd01d49548c83cf92171aceac,

title = "The virus-induced cyclic dinucleotide 2′3′-c-di-GMP mediates STING-dependent antiviral immunity in Drosophila",

abstract = "In mammals, the enzyme cGAS senses the presence of cytosolic DNA and synthesizes the cyclic dinucleotide (CDN) 2′3′-cGAMP, which triggers STING-dependent immunity. In Drosophila melanogaster, two cGAS-like receptors (cGLRs) produce 3′2′-cGAMP and 2′3′-cGAMP to activate STING. We explored CDN-mediated immunity in 14 Drosophila species covering 50 million years of evolution and found that 2′3′-cGAMP and 3′2′-cGAMP failed to control infection by Drosophila C virus in D. serrata and two other species. We discovered diverse CDNs produced in a cGLR-dependent manner in response to viral infection in D. melanogaster, including 2′3′-c-di-GMP. This CDN was a more potent STING agonist than cGAMP in D. melanogaster and it also activated a strong antiviral transcriptional response in D. serrata. Our results shed light on the evolution of cGLRs in flies and provide a basis for understanding the function and regulation of this emerging family of pattern recognition receptors in animal innate immunity.",

keywords = "c-di-GMP, cGAMP, cGAS, cGLR, Cyclic dinucleotide, Drosophila, Evolution, Pattern recognition receptor, STING, Virus",

author = "Hua Cai and Lihua Li and Slavik, {Kailey M.} and Jingxian Huang and Ting Yin and Xianlong Ai and L{\'e}na H{\'e}delin and Gabrielle Haas and Zhangmin Xiang and Yunyun Yang and Xiaoyan Li and Yuqiang Chen and Ziming Wei and Huimin Deng and Di Chen and Renjie Jiao and Nelson Martins and Carine Meignin and Kranzusch, {Philip J.} and Imler, {Jean Luc}",

note = "Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",

year = "2023",

month = sep,

day = "12",

doi = "10.1016/j.immuni.2023.08.006",

language = "English",

volume = "56",

pages = "1991--2005.e9",

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Cai, H, Li, L, Slavik, KM, Huang, J, Yin, T, Ai, X, Hédelin, L, Haas, G, Xiang, Z, Yang, Y, Li, X, Chen, Y, Wei, Z, Deng, H, Chen, D, Jiao, R, Martins, N, Meignin, C, Kranzusch, PJ & Imler, JL 2023, 'The virus-induced cyclic dinucleotide 2′3′-c-di-GMP mediates STING-dependent antiviral immunity in Drosophila', Immunity, vol. 56, no. 9, pp. 1991-2005.e9. https://doi.org/10.1016/j.immuni.2023.08.006

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T1 - The virus-induced cyclic dinucleotide 2′3′-c-di-GMP mediates STING-dependent antiviral immunity in Drosophila

AU - Cai, Hua

AU - Li, Lihua

AU - Slavik, Kailey M.

AU - Huang, Jingxian

AU - Yin, Ting

AU - Ai, Xianlong

AU - Hédelin, Léna

AU - Haas, Gabrielle

AU - Xiang, Zhangmin

AU - Yang, Yunyun

AU - Li, Xiaoyan

AU - Chen, Yuqiang

AU - Wei, Ziming

AU - Deng, Huimin

AU - Chen, Di

AU - Jiao, Renjie

AU - Martins, Nelson

AU - Meignin, Carine

AU - Kranzusch, Philip J.

AU - Imler, Jean Luc

PY - 2023/9/12

Y1 - 2023/9/12

N2 - In mammals, the enzyme cGAS senses the presence of cytosolic DNA and synthesizes the cyclic dinucleotide (CDN) 2′3′-cGAMP, which triggers STING-dependent immunity. In Drosophila melanogaster, two cGAS-like receptors (cGLRs) produce 3′2′-cGAMP and 2′3′-cGAMP to activate STING. We explored CDN-mediated immunity in 14 Drosophila species covering 50 million years of evolution and found that 2′3′-cGAMP and 3′2′-cGAMP failed to control infection by Drosophila C virus in D. serrata and two other species. We discovered diverse CDNs produced in a cGLR-dependent manner in response to viral infection in D. melanogaster, including 2′3′-c-di-GMP. This CDN was a more potent STING agonist than cGAMP in D. melanogaster and it also activated a strong antiviral transcriptional response in D. serrata. Our results shed light on the evolution of cGLRs in flies and provide a basis for understanding the function and regulation of this emerging family of pattern recognition receptors in animal innate immunity.

AB - In mammals, the enzyme cGAS senses the presence of cytosolic DNA and synthesizes the cyclic dinucleotide (CDN) 2′3′-cGAMP, which triggers STING-dependent immunity. In Drosophila melanogaster, two cGAS-like receptors (cGLRs) produce 3′2′-cGAMP and 2′3′-cGAMP to activate STING. We explored CDN-mediated immunity in 14 Drosophila species covering 50 million years of evolution and found that 2′3′-cGAMP and 3′2′-cGAMP failed to control infection by Drosophila C virus in D. serrata and two other species. We discovered diverse CDNs produced in a cGLR-dependent manner in response to viral infection in D. melanogaster, including 2′3′-c-di-GMP. This CDN was a more potent STING agonist than cGAMP in D. melanogaster and it also activated a strong antiviral transcriptional response in D. serrata. Our results shed light on the evolution of cGLRs in flies and provide a basis for understanding the function and regulation of this emerging family of pattern recognition receptors in animal innate immunity.

KW - c-di-GMP

KW - cGAMP

KW - cGAS

KW - cGLR

KW - Cyclic dinucleotide

KW - Drosophila

KW - Evolution

KW - Pattern recognition receptor

KW - STING

KW - Virus

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U2 - 10.1016/j.immuni.2023.08.006

DO - 10.1016/j.immuni.2023.08.006

M3 - Article

C2 - 37659413

AN - SCOPUS:85170412981

SN - 1074-7613

VL - 56

SP - 1991-2005.e9

JO - Immunity

JF - Immunity

IS - 9

ER -

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

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Keywords

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