The interferon-induced exonuclease, ISG20, exerts antiviral activity through upregulation of type I interferon response proteins
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ABSTRACT:
PROVIDER: PRJNA475885 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR7300141_1.fastq.gz | Fastqsanger.gz | |||
| SRR7300141_2.fastq.gz | Fastqsanger.gz | |||
| SRR7300142_1.fastq.gz | Fastqsanger.gz | |||
| SRR7300142_2.fastq.gz | Fastqsanger.gz | |||
| SRR7300143_1.fastq.gz | Fastqsanger.gz |
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Project description:Type I interferon-stimulated genes (ISGs) have critical roles in inhibiting virus replication and dissemination. Despite advances in understanding the molecular basis of ISG restriction, the antiviral mechanisms of many remain unclear. The 20 kDa ISG, ISG20, is a nuclear 3'-5'exonuclease with preference for single stranded RNA (ssRNA) and has been implicated in the IFN-mediated restriction of several RNA viruses. Although the exonuclease activity of ISG20 has been shown to degrade viral RNA in vitro, evidence has yet to be presented that virus inhibition in cells requires this activity. Here, we utilized a combination of an inducible, ectopic expression system and newly generated Isg20−/− mice to investigate mechanisms and consequences of ISG20-mediated restriction. Ectopically expressed ISG20 localized primarily to Cajal bodies in the nucleus and restricted replication of chikungunya and Venezuelan equine encephalitis viruses. Although restriction by ISG20 was associated with inhibition of translation of infecting genomic RNA, degradation of viral RNAs was not observed. Instead, translation inhibition of viral RNA was associated with ISG20-induced upregulation of over 100 other genes, many of which encode known antiviral effectors. ISG20 modulated the production of IFIT1, an ISG that suppresses translation of alphavirus RNAs. Consistent with this observation, the pathogenicity of IFIT1-sensitive alphaviruses was increased in Isg20−/− mice compared to wild-type viruses, but not in ISG20 ectopic-expressing cells. Our findings establish an indirect role for ISG20 in the early restriction of RNA virus replication by regulating expressionof other ISGs that inhibit translation and possibly other activities in the replication cycle.
2018-07-01 | GSE115729 | GEO
Project description:Type I interferon (IFN)-stimulated genes (ISGs) have critical roles in inhibiting virus replication and dissemination. Despite advances in understanding the molecular basis of ISG restriction, the antiviral mechanisms of many remain unclear. The 20-kDa ISG ISG20 is a nuclear 3'-5' exonuclease with preference for single-stranded RNA (ssRNA) and has been implicated in the IFN-mediated restriction of several RNA viruses. Although the exonuclease activity of ISG20 has been shown to degrade viral RNA in vitro, evidence has yet to be presented that virus inhibition in cells requires this activity. Here, we utilized a combination of an inducible, ectopic expression system and newly generated Isg20-/- mice to investigate mechanisms and consequences of ISG20-mediated restriction. Ectopically expressed ISG20 localized primarily to Cajal bodies in the nucleus and restricted replication of chikungunya and Venezuelan equine encephalitis viruses. Although restriction by ISG20 was associated with inhibition of translation of infecting genomic RNA, degradation of viral RNAs was not observed. Instead, translation inhibition of viral RNA was associated with ISG20-induced upregulation of over 100 other genes, many of which encode known antiviral effectors. ISG20 modulated the production of IFIT1, an ISG that suppresses translation of alphavirus RNAs. Consistent with this observation, the pathogenicity of IFIT1-sensitive alphaviruses was increased in Isg20-/- mice compared to that of wild-type viruses but not in cells ectopically expressing ISG20. Our findings establish an indirect role for ISG20 in the early restriction of RNA virus replication by regulating expression of other ISGs that inhibit translation and possibly other activities in the replication cycle.IMPORTANCE The host immune responses to infection lead to the production of type I interferon (IFN), and the upregulation of interferon-stimulated genes (ISGs) reduces virus replication and virus dissemination within a host. Ectopic expression of the interferon-induced 20-kDa exonuclease ISG20 suppressed replication of chikungunya virus and Venezuelan equine encephalitis virus, two mosquito-vectored RNA alphaviruses. Since the replication of alphavirus genomes occurs exclusively in the cytoplasm, the mechanism of nucleus-localized ISG20 inhibition of replication is unclear. In this study, we determined that ISG20 acts as a master regulator of over 100 genes, many of which are ISGs. Specifically, ISG20 upregulated IFIT1 genes and inhibited translation of the alphavirus genome. Furthermore, IFIT1-sensitive alphavirus replication was increased in Isg20-/- mice compared to the replication of wild-type viruses but not in cells ectopically expressing ISG20. We propose that ISG20 acts as an indirect regulator of RNA virus replication in the cytoplasm through the upregulation of many other ISGs.
| S-EPMC6147134 | biostudies-literature
Project description:ISG20 is an interferon-induced 3'-to-5' RNA exonuclease that acts as a broad antiviral innate defense factor. At present, the features that expose RNA to the action of ISG20 remain unclear. However recent studies have pinpointed to RNA epitranscriptomic modifications as modulators that either expose or protect viral RNAs from ISG20, raising the question as to how cellular RNAs, on which these modifications are abundant, cope with ISG20. To obtain an unbiased perspective on this issue, we used RNAseq to pinpoint to the RNA elements that regulate the balance between susceptibility and resistance to ISG20.
2023-06-01 | GSE233792 | GEO
Project description:Hepatitis B virus (HBV) persists by depositing a covalently closed circular DNA (cccDNA) in the nucleus of infected cells that cannot be targeted by available antivirals. Cytokine treatments can diminish HBV cccDNA via APOBEC3-mediated deamination. Here we show that overexpression of APOBEC3A alone, however, was not sufficient to reduce cccDNA in HBV-infected cells. This required addition of interferon indicating that cccDNA degradation requires an additional, interferon-stimulated gene (ISG). Transcriptome analyses identified ISG20 as the only type I and II interferon-induced, nucleus-resident protein with annotated nuclease activity. ISG20 expression was detected in human livers in acute, self-limiting but not in chronic hepatitis B. ISG20 depletion abolished the interferon-induced loss of cccDNA, and co-expression of ISG20 and APOBEC3A was sufficient to diminish cccDNA. In conclusion, non-cytolytic HBV cccDNA decline requires induction of a deaminase and nuclease. Our findings highlight that ISGs cooperate for their antiviral function and this cooperativity may be explored for therapeutic targeting.
2021-04-22 | PXD019285 | Pride
Project description:Hepatitis B virus (HBV) persists by depositing a covalently closed circular DNA (cccDNA) in the nucleus that cannot be targeted by available antivirals. Cytokine treatments can purge cccDNA from the nucleus of infected cells by APOBEC3-mediated deamination. cccDNA levels in HBV-infected cells were not reduced by overexpression of APOBEC3A alone, but only after simultaneous addition of interferon. This indicated the need of an additional, interferon-induced factor (ISG). Microarray analysis identified ISG20 as the only nuclease located to the nucleus induced by type I and II interferons. ISG20 was confirmed to be expressed in acute, self-limiting but not in chronic hepatitis B in human livers. ISG20 knockdown abolished the interferon-induced loss of cccDNA, and co-expression of ISG20 and APOBEC3A was sufficient to diminish cccDNA without further treatment. To conclude, nucleolar ISG20 was identified as the nuclease contributing to interferon-induced purging of HBV cccDNA, opening new avenues for antiviral targeting.
2020-07-22 | GSE134929 | GEO
Project description:Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the highest rates of recurrence, metastasis and patient mortality due to lack of effective targeted therapies. In this study, we demonstrate that ISG20 expression is induced by hypoxia and directly targeted by HIF-1 for transcription in TNBC cells. ISG20 functions as RNA exonuclease to target mRNAs for degradation, resulting in breast cancer stem cell specification and lung metastasis, and also cancer cell immune evasion. Mostly importantly, ISG20 silencing could markedly increase the sensitivity of TNBC to anti-PD1 immune checkpoint blockade (ICB) in a mouse model. Our data suggested that, in combination with immunotherapy, targeting ISG20 might be an effective strategy for TNBC treatment.
2025-11-25 | GSE287164 | GEO
Project description:We screened a number of interferon inducible genes that may be involved in impeding HBV replication and found an anti-HBV activity in ISG20. ISG20 is an IFN-inducible 3’- to 5’-exonuclease, that degrades DNA and RNA and reduces antigen production in hepatocyte-derived cells A range of candidate genes whose expression was dependent on type I IFN stimulation were identified by gene arrays
2016-06-10 | GSE75690 | GEO
Project description:We screened a number of interferon inducible genes that may be involved in impeding HBV replication and found an anti-HBV activity in ISG20. ISG20 is an IFN-inducible 3â??- to 5â??-exonuclease, that degrades DNA and RNA and reduces antigen production in hepatocyte-derived cells A range of candidate genes whose expression was dependent on type I IFN stimulation were identified by gene arrays Total RNA from CD8α+ DCs was extracted from mouse spleens 8h after polyI:C (50 μg) stimulation by RNeasyTM kit. Total RNA (10 μg) from each sample was used to prepare cRNA. Gene expression was analyzed with GeneChipTM
2016-06-10 | E-GEOD-75690 | biostudies-arrayexpress
Project description:Identification of ISG20 as the nuclease involved in interferon-induced decline of hepatitis B virus cccDNA
| PRJNA556822 | ENA
Project description:Analysis of differentially expressed genes (DEGs) revealed a striking upregulation of interferon genes in P301S, compared to non-transgenic hippocampi, and enrichment of transcription factor motifs of interferon-response factors (IRFs) and interferon-sensitive response elements (ISREs). Cgas deletion reduced the induction of a subset of tau-stimulated inflammatory and cytokine expression including interferon stimulated genes such as Stat1, Ddx60, Isg20, Rnf213, Parp12, Ifi35, and Sp100. Thus, microglial cGAS promotes IFN-I expression in response to tau.
2023-04-26 | GSE226380 | GEO