Dataset Information

Investigating the Evolution of Drosophila STING-dependent Antiviral Innate Immunity by Multispecies Comparison of 2'3'-cGAMP Responses.

ABSTRACT: Viruses represent a major threat for all animals, which defend themselves through induction of a large set of virus-stimulated genes that collectively control the infection. In vertebrates, these genes include interferons that play a critical role in the amplification of the response to infection. Virus- and interferon-stimulated genes include restriction factors targeting the different steps of the viral replication cycle, in addition to molecules associated with inflammation and adaptive immunity. Predictably, antiviral genes evolve dynamically in response to viral pressure. As a result, each animal has a unique arsenal of antiviral genes. Here, we exploit the capacity to experimentally activate the evolutionarily conserved STING signaling pathway by injection of the cyclic dinucleotide 2'3'-cGAMP into flies to define the repertoire of STING-regulated genes in ten Drosophila species, spanning 50 million years of evolution. Our data reveal a set of conserved STING-regulated factors, including STING itself, a cGAS-like receptor, the restriction factor pastrel, and the antiviral protein Vago, but also two key components of the antiviral RNA interference pathway, Dicer-2 and Argonaute2. In addition, we identify unknown species- or lineage-specific genes that have not been previously associated with resistance to viruses. Our data provide insight on the core antiviral response in Drosophila flies and pave the way for the characterization of previously unknown antiviral effectors.

SUBMITTER: Hedelin L

PROVIDER: S-EPMC10917227 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Investigating the Evolution of Drosophila STING-Dependent Antiviral Innate Immunity by Multispecies Comparison of 2'3'-cGAMP Responses.

Hédelin Léna L Thiébaut Antonin A Huang Jingxian J Li Xiaoyan X Lemoine Aurélie A Haas Gabrielle G Meignin Carine C Cai Hua H Waterhouse Robert M RM Martins Nelson N Imler Jean-Luc JL

Molecular biology and evolution 20240301 3

Viruses represent a major threat to all animals, which defend themselves through induction of a large set of virus-stimulated genes that collectively control the infection. In vertebrates, these genes include interferons that play a critical role in the amplification of the response to infection. Virus- and interferon-stimulated genes include restriction factors targeting the different steps of the viral replication cycle, in addition to molecules associated with inflammation and adaptive immuni ...[more]

PMID: 38377349

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Project description:BackgroundO-GlcNAcylation modification affects multiple physiological and pathophysiolocal functions of cells. Altered O-GlcNAcylation was reported to participate in antivirus response. Stimulator of interferon genes (STING) is an adaptor mediating DNA virus-induced innate immune response. Whether STING is able to be modified by O-GlcNAcylation and how O-GlcNAcylation affects STING-mediated anti-DNA virus response remain unknown.MethodsMetabolomics analysis was used for detecting metabolic alterations in HSV-1 infection cells. Succinylated wheat germ agglutinin (sWGA), co-immunoprecipitation, and pull-down assay were employed for determining O-GlcNAcylation. Mutagenesis PCR was applied for the generation of STING mutants. WT and Sting1-/- C57BL/6 mice (KOCMP-72512-Sting1-B6NVA) were infected with HSV-1 and treated with O-GlcNAcylation inhibitor for validating the role of STING O-GlcNAcylation in antiviral response.ResultsSTING was functionally activated by O-GlcNAcylation in host cells challenged with HSV-1. We demonstrated that this signaling event was initiated by virus infection-enhanced hexosamine biosynthesis pathway (HBP). HSV-1 (or viral DNA mimics) promotes glucose metabolism of host cells with a marked increase in HBP, which provides donor glucosamine for O-GlcNAcylation. STING was O-GlcNAcylated on threonine 229, which led to lysine 63-linked ubiquitination of STING and activation of antiviral immune responses. Mutation of STING T229 to alanine abrogated STING activation and reduced HSV-1 stimulated production of interferon (IFN). Application of 6-diazo-5-oxonorleucine (DON), an agent that blocks the production of UDP-GlcNAc and inhibits O-GlcNAcylation, markedly attenuated the removal of HSV-1 in wild type C57BL/6 mice, leading to an increased viral retention, elevated infiltration of inflammatory cells, and worsened tissue damages to those displayed in STING gene knockout mice. Together, our data suggest that STING is O-GlcNAcylated in HSV-1, which is crucial for an effective antiviral innate immune response.ConclusionHSV-1 infection activates the generation of UDP-Glc-NAc by upregulating the HBP metabolism. Elevated UDP-Glc-NAc promotes the O-GlcNAcylation of STING, which mediates the anti-viral function of STING. Targeting O-GlcNAcylation of STING could be a useful strategy for antiviral innate immunity.

Dataset Information

Investigating the Evolution of Drosophila STING-dependent Antiviral Innate Immunity by Multispecies Comparison of 2'3'-cGAMP Responses.

Publications

Investigating the Evolution of Drosophila STING-Dependent Antiviral Innate Immunity by Multispecies Comparison of 2'3'-cGAMP Responses.

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