CGAS maintains basal antiviral state
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ABSTRACT:
PROVIDER: PRJNA839440 | ENA |
REPOSITORIES: ENA
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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:The hypothesis tested was that lentiviral driven cGAS expression activates antiviral gene expression. Cells were transduced with lentiviruses expressing cGAS or a control (firefly luciferase). Total RNA was harvested 48 h post-transduction and processed for Illumina BeadArray.
2013-12-01 | E-GEOD-52241 | biostudies-arrayexpress
Project description:The cyclic oligonucleotide-based anti-phage signalling system (CBASS) is a typeof innate prokaryotic immune system. Composed of a cyclic GMP-AMP synthase (cGAS) and CBASS-associated proteins, CBASS utilizes cyclic oligonucleotides to activate antiviral immunity. One major class of CBASS contains a homolog of eukaryotic ubiquitin-conjugating enzymes, which is either an E1-E2 fusion or a single E2. However, the functions of single E2s in CBASS remain elusive. Here, we report that a bacterial E2 enzyme regulates cGAS by imitating the ubiquitination cascade. This includes the processing of the cGAS C-terminus, conjugation of cGAS to a cysteine residue, ligation of cGAS to a lysine residue, cleavage of the isopeptide bond, and poly-cGASylation. The poly-cGASylation activates cGAS to produce cGAMP, which acts as an antiviral signal and leads to cell death. Thus, our findings reveal a unique regulatory role of E2 in CBASS.
2024-02-27 | PXD050178 | iProX
Project description:Although the pathogen recognition receptor pathways that activate cell-intrinsic antiviral responses are well delineated, less is known about how the host regulates this response to prevent sustained signaling and possible immune-mediated damage. Using a genome-wide CRISPR-Cas9 screening approach to identify host factors that modulate interferon (IFN) stimulated gene (ISG) expression, we identified the DNA binding protein Barrier-to-autointegration factor 1 (Banf1), a previously described inhibitor of retrovirus integration, as a modulator of basal cell-intrinsic immunity. Ablation of Banf1 by gene editing resulted in enhanced chromatin accessibility of host defense genes and increased expression of ISGs including Oas2, Rsad2 (viperin), Ifit1, ISG15 and Cxcl10. The phenotype in Banf1-deficient cells occurred through a cGAS, STING, and IRF3-dependent signaling axis, was associated with reduced infection of RNA and DNA viruses, and was reversed in Banf1 complemented cells. Confocal microscopy and biochemical studies revealed that a loss of expression of Banf1 resulted in higher level of cytosolic double-stranded DNA at baseline. Our study identifies an undescribed role for Banf1 in regulating levels of cytoplasmic DNA and cGAS-dependent ISG homeostasis and suggests possible therapeutic directions for promoting or inhibiting cell-intrinsic innate immune responses.
2020-12-31 | GSE141386 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE32362: Hydroxylation of 5-methylcytosine by TET2 maintains the active state of the mammalian HOXA cluster (Illumina HumanMethylation450 BeadChip) GSE33129: Hydroxylation of 5-methylcytosine by TET2 maintains the active state of the mammalian HOXA cluster (Illumina HiSeq2000 sequencing) Refer to individual Series
2012-05-02 | E-GEOD-33130 | biostudies-arrayexpress
Project description:The cytosolic DNA sensor cyclic GMP-AMP (cGAMP) synthetase (cGAS) has emerged as a fundamental component fueling the anti-pathogen immunity. Because of its pivotal role in initiating innate immune response, the activity of cGAS must be tightly fine-tuned to maintain immune homeostasis in antiviral response. Here, we reported that neddylation modification was indispensable for appropriate cGAS-STING signaling activation. Blocking neddylation pathway using neddylation inhibitor MLN4924 substantially impaired the induction of type I interferon and proinflammatory cytokines, which was selectively dependent on Nedd8 E2 enzyme Ube2m. We further found that deficiency of the Nedd8 E3 ligase Rnf111 greatly attenuated DNA-triggered cGAS activation while not affecting cGAMP induced activation of STING, demonstrating that Rnf111 was the Nedd8 E3 ligase of cGAS. We further identified Lys231 and Lys421 as the key neddylation sites in human cGAS. Mechanistically, Rnf111 interacted with and polyneddylated cGAS, which in turn promoted its dimerization and enhanced the DNA-binding ability, leading to proper cGAS-STING pathway activation. In the same line, the Ube2m or Rnf111 deficiency mice exhibited severe defects in innate immune response and were susceptible to HSV-1 infection. Collectively, our study uncovered a vital role of the Ube2m-Rnf111 neddylation axis in promoting the activity of the cGAS-STING pathway and highlighted the importance of neddylation modification in antiviral defense.
2021-02-22 | PXD024088 | Pride
Project description:The hypothesis tested was that lentiviral driven cGAS expression activates antiviral gene expression.
2013-12-01 | GSE52241 | GEO
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Project description:Barrier-to-autointegration factor 1 protects against a basal cGAS-STING response
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Project description:Transcription Factor Redundancy Ensures Induction of the Antiviral State
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