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The cGAS-STING pathway operates through the production of the cyclic dinucleotide (CDN) cGAMP and regulates interferon production and induction of antiviral immunity in mammals. The discovery that animals from corals to humans express numerous cGAS-like receptors (cGLRs) suggests that they play a fundamental role in innate immunity. A paper published in the journal Immunity reveals that cGLRs rapidly evolve in Drosophila flies, producing at least four CDNs in response to viral infections. One of these, 2′3′-c-di-GMP, was previously unknown and is a better STING agonist than cGAMP in Drosophila.

Figure : Drosophila flies express up to seven cGLR receptors and produce several distinct cyclic dinucleotides in response to viral infection.

Innate immunity, the first line of defense against infection in animals, relies on families of receptors called pattern recognition receptors (PRRs), which recognize characteristic molecular patterns. In the case of viruses, which expose few targets to the immune system, it is generally nucleic acids, DNA or RNA, that are recognized. In mammals, PRRs of the Toll-like receptor (TLR) or RIG-I-like receptor (RLR) families alert the cell to the presence of RNA or DNA in its cytoplasm. In addition, the cGAS enzyme detects the presence of DNA in the cell cytosol, triggering the production of a cyclic dinucleotide (CDN), 2′3′-cyclic GMP-AMP (2′3′-cGAMP). This will bind to the STING protein, which will then activate kinases that phosphorylate the transcription factors NF-kB and IRF3 to induce interferon synthesis.

In the fruit fly Drosophila melanogaster, a model organism, two cGAS-related receptors, cGAS-like receptor (cGLR)1 and cGLR2, produce 2′3′-cGAMP but also 3′2′-cGAMP to activate STING and antiviral immunity. In a collaboration between Chinese (Guangzhou Medical University), French (CNRS, Strasbourg university) and American (Harvard university) teams, the researchers explored the immune response triggered by DNCs in 14 different Drosophila species, spanning 50 million years of evolution. Surprisingly, they observed that neither 2′3′-cGAMP nor 3′2′-cGAMP were able to protect flies of three species, including D. serrata. This result led the scientists to investigate whether other CDNs existed. They were thus able to show that several CDNs were produced in D. melanogaster flies in response to viral infections, including 2′3′-c-di-GMP, which had not been described in nature until now. This CDN is a better STING agonist than cGAMP in D. melanogaster, and also activates a strong antiviral response in the species D. serrata.

This work sheds new light on an emerging family of innate immunity receptors, and illustrates how evolutionary approaches exploiting biodiversity can lead to the discovery of new small molecules that regulate viral infections.

To know more :

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

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

Published in Immunity (12 septembre 2023)

Contact scientist :

Jean-Luc Imler

Professor, University of Strasbourg
03 88 41 70 37 / 06 32 27 86 08

Modèles Insectes d’Immunité Innée (CNRS)
Institut de Biologie Moléculaire et Cellulaire
2 allée Konrad Roentgen, 67084 Strasbourg Cedex

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