Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1089487 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28385174_1.fastq.gz | Fastqsanger.gz | |||
| SRR28385174_2.fastq.gz | Fastqsanger.gz | |||
| SRR28385175_1.fastq.gz | Fastqsanger.gz | |||
| SRR28385175_2.fastq.gz | Fastqsanger.gz | |||
| SRR28385176_1.fastq.gz | Fastqsanger.gz |
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Project description:Centromeric DNA amplification triggered by viral proteins activates nuclear cGAS
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Project description:The cGAS-cGAMP-STING pathway is crucial for antiviral immunity. While cytosolic cGAS detects viral DNA, most DNA viruses shield their genome and invade the nucleus, where chromatin restricts cGAS activation. How viruses may activate nuclear cGAS is not well understood. Here, we show that several herpesvirus proteins trigger nuclear cGAS activation by perturbing centromeres, where cGAS is enriched. The herpes simplex virus type 1 (HSV-1) ubiquitin ligase ICP0, which degrades centromeric proteins, promotes centromeric DNA amplification through the translesion DNA synthesis (TLS) pathway in quiescent monocyte-derived cells, thereby activating nuclear cGAS. During infection, HSV-1 evades this detection by also expressing UL36USP, a suppressor of TLS. Similarly to ICP0, the cytomegalovirus IE1 protein causes centromeric DNA amplification and cGAS activation. We define this mechanism as Viral-Induced Centromeric DNA Amplification and Recognition (VICAR), uncovering a non-mitotic, immune-activating role of centromeres.
2025-05-25 | GSE254979 | GEO
Project description:Cytosolic DNA activates cyclic GMP-AMP (cGAMP) synthase (cGAS), an innate immune sensor pivotal in anti-microbial defense, senescence, auto-immunity and cancer. cGAS is considered a sequence-independent DNA sensor with limited access to nuclear DNA because of compartmentalization. However, the nuclear envelope is a dynamic barrier and cGAS is present in the nucleus. Here, we identify determinants of nuclear cGAS localization and activation. We show that nuclear-localized cGAS synthesizes cGAMP and induces innate immune activation of dendritic cells, but cGAMP levels are 200-fold lower than following transfection with exogenous DNA. Using cGAS ChIP-seq and a GFP-cGAS knock-in mouse, we find nuclear cGAS enrichment on centromeric satellite DNA, confirmed by imaging, and to a lesser extent with LINE elements. The non-enzymatic N-terminal domain of cGAS determines nucleo-cytoplasmic localization, enrichment on centromeres and activation of nuclear-localized cGAS. These results reveal a preferential functional association of nuclear cGAS with centromeres.
2019-02-27 | GSE125432 | GEO
Project description:Cytosolic DNA activates cyclic GMP-AMP (cGAMP) synthase (cGAS), an innate immune sensor pivotal in anti-microbial defense, senescence, auto-immunity and cancer. cGAS is considered a sequence-independent DNA sensor with limited access to nuclear DNA because of compartmentalization. However, the nuclear envelope is a dynamic barrier and cGAS is present in the nucleus. Here, we identify determinants of nuclear cGAS localization and activation. We show that nuclear-localized cGAS synthesizes cGAMP and induces innate immune activation of dendritic cells, but cGAMP levels are 200-fold lower than following transfection with exogenous DNA. Using cGAS ChIP-seq and a GFP-cGAS knock-in mouse, we find nuclear cGAS enrichment on centromeric satellite DNA, confirmed by imaging, and to a lesser extent with LINE elements. The non-enzymatic N-terminal domain of cGAS determines nucleo-cytoplasmic localization, enrichment on centromeres and activation of nuclear-localized cGAS. These results reveal a preferential functional association of nuclear cGAS with centromeres.
2019-02-27 | GSE125431 | GEO
Project description:We identified RAD51 and RPA1A as partners of virus-encoded Rep protein. The two DNA repair proteins showed increased binding to heterochromatic regions and defense-related genes in atxr5 atxr6 vs wild-type plants. Consequently, the proteins had reduced binding to viral DNA in the mutant, thus hampering viral amplification. Additionally, RAD51 recruitment to the host genome arose via BRCA1, HOP2, and CYCB1;1, and this recruitment was essential for viral resistance in atxr5 atxr6. Thus, Geminiviruses adapt to healthy plants by hijacking DNA repairing pathways, whereas the unstable genome, triggered by lack of H3.1K27me1, could retain DNA repairing proteins to suppress viral infection in atxr5 atxr6.
2023-10-17 | GSE235053 | GEO
Project description:Viral DNA sensing is an essential component of mammalian innate immune response. Upon binding viral DNA, the cyclic-GMP-AMP synthase (cGAS) catalyzes the production of cyclic dinucleotides to induce type I interferons. However, little is known about how cGAS is homeostatically maintained or regulated upon infection. Here, we define cytoplasmic cGAS interactions with cellular and viral proteins upon herpes simplex virus (HSV-1) infection in primary human fibroblasts. We compare several HSV-1 strains (wild-type, d109, d106) that induce cytokine responses and apoptosis, and place cGAS interactions in the context of temporal proteome alterations using isobaric-labeling mass spectrometry. Follow-up analyses establish a functional interaction between cGAS and 2â??-5â??-oligoadenylate synthase-like protein OASL. The OAS-like domain interacts with the cGAS Mab21 domain, while the OASL ubiquitin-like domain further inhibits cGAS-mediated interferon response. Our findings explain how cGAS may be inactively maintained in cellular homeostasis, with OASL functioning as a negative feedback loop for cytokine induction.
| MSV000084374 | MassIVE
Project description:Detection of viruses by innate immune sensors induces protective antiviral immunity. The viral DNA sensor cGAS is necessary for detection of HIV by human dendritic cells and macrophages. However, synthesis of HIV DNA during infection is not sufficient for immune activation. The capsid protein, which associates with viral DNA, has a pivotal role in enabling cGAS-mediated immune activation. We now find that NONO is an essential sensor of the HIV capsid in the nucleus. NONO protein directly binds capsid with higher affinity for weakly pathogenic HIV-2 than highly pathogenic HIV-1. Upon infection, NONO is essential for cGAS activation by HIV and cGAS association with HIV DNA in the nucleus. NONO recognizes a conserved region in HIV capsid with limited tolerance for escape mutations. Detection of nuclear viral capsid by NONO to promote DNA sensing by cGAS reveals an innate strategy to achieve distinction of viruses from self in the nucleus.
2018-09-28 | GSE109554 | GEO
Project description:Upon recognition of aberrantly located DNA, the innate immune sensor cGAS activates STING/IRF-3-driven antiviral responses. Here we characterized the ability of a specific variant of the cGAS-encoding gene MB21D1, rs610913, to alter cGAS-mediated DNA sensing and viral infection. rs610913 is a frequent G>T polymorphism resulting in a P261H exchange in the cGAS protein. Data from the International Collaboration for the Genomics of HIV suggested that rs610913 nominally associates with HIV-1 acquisition in vivo. Molecular modeling of cGAS(P261H) hinted towards the possibility for an additional binding site for a potential cellular co-factor in cGAS dimers. However, cGAS(WT) or cGAS(P261H)-reconstituted THP-1 cGAS KO cells shared steady-state expression of interferon-stimulated genes (ISGs), as opposed to cells expressing the enzymatically inactive cGAS(G212A/S213A). Accordingly, cGAS(WT) and cGAS(P261H) cells were less susceptible to lentiviral transduction and infection with HIV-1, HSV-1, and Chikungunya virus as compared to cGAS KO- or cGAS(G212A/S213A) cells. Upon DNA challenge, innate immune activation appeared to be mildly reduced upon expression of cGAS(P261H) compared to cGAS(WT). Finally, DNA challenge of PBMCs from donors homozygously expressing rs610913 provoked a trend towards a slightly reduced type I IFN response as compared to PBMCs from GG donors. Taken together, the steady-state activity of cGAS maintains a base-line antiviral state rendering cells more refractory to ISG-sensitive viral infections. rs610913 failed to grossly differ phenotypically from the wild-type gene, suggesting that cGAS(P261H) and wild-type cGAS share a similar ability to sense viral infections in vivo.
2022-05-25 | GSE203334 | GEO
Project description:Viruses have evolved diverse immune evasion strategies including targeting host pattern recognition receptors. The role of viral non-coding RNAs in modulating PRR activity is unclear. Here, we show that human cytomegalovirus (HCMV) produces long non-coding RNA4.9 that counteracts nuclear cyclic GMP-AMP synthase (cGAS)-mediated immune response to facilitate viral infection in primary human foreskin fibroblasts (HFFs). RNA4.9 interacts with host cGAS via its 75-nucleotide (nt) RNA region with predicted hairpin loops. Binding of RNA4.9 to cGAS inhibits cGAS enzymatic activity and downstream interferon response, and facilitates productive viral replication. Sterically blocking the folding of 75-nt region with antisense oligonucleotides during HCMV infection restores cGAS activity and impairs viral replication. We also found that the specific localization of RNA4.9, which concentrates near HCMV DNA, is correlated with its efficient binding to cGAS and subsequent immune suppression. Our findings demonstrate viral non-coding RNAs as critical cGAS regulators and potential therapeutic targets.
2025-06-11 | GSE268887 | GEO
Project description:Viruses have evolved diverse immune evasion strategies including targeting host pattern recognition receptors. The role of viral non-coding RNAs in modulating PRR activity is unclear. Here, we show that human cytomegalovirus (HCMV) produces long non-coding RNA4.9 that counteracts nuclear cyclic GMP-AMP synthase (cGAS)-mediated immune response to facilitate viral infection in primary human foreskin fibroblasts (HFFs). RNA4.9 interacts with host cGAS via its 75-nucleotide (nt) RNA region with predicted hairpin loops. Binding of RNA4.9 to cGAS inhibits cGAS enzymatic activity and downstream interferon response, and facilitates productive viral replication. Sterically blocking the folding of 75-nt region with antisense oligonucleotides during HCMV infection restores cGAS activity and impairs viral replication. We also found that the specific localization of RNA4.9, which concentrates near HCMV DNA, is correlated with its efficient binding to cGAS and subsequent immune suppression. Our findings demonstrate viral non-coding RNAs as critical cGAS regulators and potential therapeutic targets.
2025-06-12 | GSE270524 | GEO