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ROXANNE2
cGLR-STING mediated antiviral immunity in drosophila
FunderFrench National Research Agency (ANR)
Funder Contribution €386,985.00
DurationFrom 02 Jan 2023
Project codeANR-22-CE15-0019
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Description
In the course of the ANR-funded ROXANNE (2017-2021) project, we have characterized a novel innate immunity pathway functioning in the control of viral infections in the model organism drosophila. This pathway involves the evolutionarily conserved molecule STING, which activates an NF-kB-dependent transcriptional program that mediates resistance to viral infection. We have recently identified two cGAS-like receptors (cGLRs) involved in the activation of this pathway, through the production of three cyclic dinucleotides (CDNs), 2'3'-cGAMP, 3'2'-cGAMP and 2'3'-c-di-AMP. The goal of this application is to address the new questions raised by this discovery. We will investigate the precise function of the cGLRs in vivo, determining the tissues in which they are active, the cell compartment where they operate and how they integrate their activity with the small interfering (si) RNA pathway, which was until now thought to be the major antiviral mechanism in flies. In particular, we will attempt to identify the ligand activating cGLR2 and the mechanism by which the receptor is activated. In a second aim, we will investigate the function of the three CDNs, addressing their possible role as immunotransmitters in systemic immunity. Finally, we will address the mechanism by which STING activates NF-kB, a question that remains ill characterized in mammals. Overall, this proposal aims at exploiting the resources of the drosophila model to shed light on still poorly understood or emerging aspects of cGAS-STING biology.
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In the course of the ANR-funded ROXANNE (2017-2021) project, we have characterized a novel innate immunity pathway functioning in the control of viral infections in the model organism drosophila. This pathway involves the evolutionarily conserved molecule STING, which activates an NF-kB-dependent transcriptional program that mediates resistance to viral infection. We have recently identified two cGAS-like receptors (cGLRs) involved in the activation of this pathway, through the production of three cyclic dinucleotides (CDNs), 2'3'-cGAMP, 3'2'-cGAMP and 2'3'-c-di-AMP. The goal of this application is to address the new questions raised by this discovery. We will investigate the precise function of the cGLRs in vivo, determining the tissues in which they are active, the cell compartment where they operate and how they integrate their activity with the small interfering (si) RNA pathway, which was until now thought to be the major antiviral mechanism in flies. In particular, we will attempt to identify the ligand activating cGLR2 and the mechanism by which the receptor is activated. In a second aim, we will investigate the function of the three CDNs, addressing their possible role as immunotransmitters in systemic immunity. Finally, we will address the mechanism by which STING activates NF-kB, a question that remains ill characterized in mammals. Overall, this proposal aims at exploiting the resources of the drosophila model to shed light on still poorly understood or emerging aspects of cGAS-STING biology.
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