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

Immunity. 2023 Sep 12;56(9):1991-2005.e9. doi: 10.1016/j.immuni.2023.08.006. Epub 2023 Sep 1.

Authors

Hua Cai¹, Lihua Li², Kailey M Slavik³, Jingxian Huang², Ting Yin², Xianlong Ai², Léna Hédelin⁴, Gabrielle Haas⁴, Zhangmin Xiang⁵, Yunyun Yang⁵, Xiaoyan Li², Yuqiang Chen², Ziming Wei², Huimin Deng², Di Chen², Renjie Jiao², Nelson Martins⁴, Carine Meignin⁴, Philip J Kranzusch⁶, Jean-Luc Imler⁷

Affiliations

¹ Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, China. Electronic address: chjorbe@hotmail.com.
² Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, China.
³ Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
⁴ Université de Strasbourg, CNRS UPR9022, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France.
⁵ Guangdong Provincial Engineering Research Center for Ambient Mass Spectrometry, Guangdong Provincial Key Laboratory of Chemical Measurement and Emergency Test Technology, Institute of Analysis, Guangdong Academy of Sciences (China National Analytical Center Guangzhou), Guangzhou, China.
⁶ Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Electronic address: philip_kranzusch@dfci.harvard.edu.
⁷ Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, China; Université de Strasbourg, CNRS UPR9022, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France.

PMID: 37659413
DOI: 10.1016/j.immuni.2023.08.006

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: Drosophila; STING; c-di-GMP; cGAMP; cGAS; cGLR; cyclic dinucleotide; evolution; pattern recognition receptor; virus.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Antiviral Agents*
Cyclic GMP
Drosophila melanogaster
Drosophila*
Mammals

Substances

Antiviral Agents
bis(3',5')-cyclic diguanylic acid
Cyclic GMP

Abstract

Publication types

MeSH terms

Substances

Grants and funding