Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Centromeric DNA amplification triggered by viral proteins activates nuclear cGAS

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE254979 | GEO | 2025/05/25

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Nuclear GFP ChIP-seq from human Monocyte Derived Dendritic Cells transduced with GFP-NLS-cGAS or GFP-NLS

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

Nuclear GFP ChIP-seq from bone marrow-derived dendritic cells of GFP-cGAS knock-In mice

2019-02-27 | GSE125432 | GEO

Centromeric DNA amplification triggered by viral proteins activates nuclear cGAS

Project description:Centromeric DNA amplification triggered by viral proteins activates nuclear cGAS

| PRJNA1072735 | ENA

Project description:Centromeric DNA amplification triggered by viral proteins activates nuclear cGAS

| PRJNA1089487 | ENA

Immediate early proteins of herpes simplex virus transiently repress viral transcription before subsequent activation.

Project description:This study was undertaken to further clarify the roles of HSV-1 immediately early (IE) genes ICP4, ICP0, and ICP22 in early viral transcription. Precision nuclear Run On followed by deep Sequencing (PRO-Seq) was used to identify sites of Pol activity to high resolution on the genomes of HSV-1 viruses bearing mutations in a0, a4 or a22/US1, and corresponding viruses in which these loci were genetically restored. The results indicated that prior to initiating activation of transcription, IE genes first mediate transcriptional repression.

2022-10-18 | GSE202363 | GEO

Identification of SLFN5 as an intrinsic inhibitor of viral transcription antagonized by the herpes simplex virus ubiquitin ligase ICP0

Project description:Intrinsic antiviral host factors are proteins that can confer cellular defense by limiting virus replication. Viruses hijack ubiquitin machinery to modify the cellular proteome to subvert these host defenses. The herpes simplex virus 1 (HSV-1) expresses ICP0, which functions as an E3 ubiquitin ligase required to promote infection. Cellular substrates of ICP0 have been discovered as host barriers to infection but the mechanisms for inhibition of viral gene expression are not fully understood. To identify new restriction factors antagonized by ICP0, we compared the proteomes associated with viral DNA (vDNA) during HSV-1 infection with wild-type (WT) virus and a mutant lacking functional ICP0 (ΔICP0). We identified the cellular protein Schlafen 5 (SLFN5) as a new ICP0 target that binds vDNA during HSV-1 ΔICP0 infection. We demonstrated that ICP0 mediates ubiquitination of SLFN5 which leads to its proteasomal degradation. In the absence of ICP0, we demonstrate SLFN5 binds vDNA to represses HSV-1 transcription by limiting accessibility of RNA polymerase II to viral promoters. These results identify SLFN5 as a new restriction factor that inhibits viral transcription and document the first viral countermeasure reported to overcome SLFN antiviral activity.

2020-09-14 | PXD018773 | Pride

Identification of viral and host targets of miR-138 by PAR-CLIP analysis of herpes simplex virus 2 infected 293T cells

Project description:Like herpes simplex virus 1 (HSV-1) ICP0 mRNA, HSV-2 ICP0 mRNA is predicted to be targeted by a host neuron-specific microRNA, miR-138. This study was designed to confirm the interaction between HSV-2 ICP0 mRNA and miR-138, and to identify other potential viral and host targets of miR-138 during HSV-2 infection. We performed PAR-CLIP on HSV-2 infected 293T cells overexpressing miR-138 in comparisin to control 293T cells. The results confirmed ICP0 as miR-138's targets, and also identified some other potential viral and host targets of miR-138.

2021-11-01 | GSE155402 | GEO

Multifaceted roles of RAP80 during the Herpes simplex virus 1 life cycle

Project description:Herpes simplex virus 1 (HSV-1) is a widespread human pathogen that establishes lifelong infections, but understanding precise activity at each infection stage remains challenging. HSV-1 utilizes ubiquitination pathways to modulate cellular factors to facilitate its replication cycle, however, elucidating the cascades that follow host protein degradation and the subsequent impact on the host-virus equilibrium continues to be a complex endeavor. Here we reveal the multifaceted role of the DNA damage response protein RAP80 throughout HSV-1’s infection cycle. In early stages, RAP80 inhibits HSV-1 transcription by directly binding to the viral genome, blocking ICP4 (viral protein) binding to transcription factors. This interaction is regulated by phase separation via an intricate interplay between RAP80 and ICP0/ICP4. As infection progresses, the viral E3 ligase ICP0 degrades RAP80, dissolving phase separation, and allowing the formation of a mature viral replication compartment. In late infection stages, RAP80 is deubiquitinated by the viral deubiquitinase UL36USP, which restores cellular homeostasis and promotes HSV-1 survival. This process involves modulating the R-loop-cGAS-apoptosis pathway. These findings underscore the dynamic interplay between viral and host factors and the complex mechanisms used by HSV-1 to subvert host defenses, offering practical implications for the future development of antiviral strategies.

2024-11-13 | GSE281836 | GEO

Identification of targets of miR-138 in Neuro-2a and 293T cells by RNAseq

Project description:We previously showed that miR-138 can repress herpes simplex virus 1 (HSV-1) ICP0 expression by binding to ICP0 mRNA. However, in this study we found that miR-138 can also repress viral gene expression independent of ICP0. We did not find other confirmed viral targets of miR-138. Therefore we conducted these RNAseq experiments (in combination with PAR-CLIP experiments whose results are uploaded separately) to identify host targets of miR-138 in two cell lines to explain the ICP0-independent effects on HSV-1 gene expression.

2020-04-27 | GSE127502 | GEO

DNA-PK Phosphoproteomic Profiling during HSV-1 and DNA

Project description:HFF cells were infected with ICP0 RF HSV-1 (MOI 5), treated with bleomycin (10mg/mL), or left untreated as a control. Nu-7441 (DNA-PK inhibitor; 2uM)or DMSO (Control) was applied after 1 hour then samples were harvested after 1 hour for bleomycin treated cells or 6 hours for HSV-1 infected cells.

2024-10-07 | PXD044489 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data