The ribonuclease <scp>l</scp>‐dependent antiviral roles of human 2′,5′‐oligoadenylate synthetase family members against hepatitis C virus

Kwon, Young Chan; Kang, Ju Il; Hwang, Soon B.; Ahn, Byung Yoon

doi:10.1016/j.febslet.2012.11.010

Cited by 51 publications

(44 citation statements)

References 31 publications

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“…It has been reported that OAS3 is constitutively expressed in Huh7 cells, and is significantly induced following IFN treatment. OAS3 may exert its anti-HCV replication through the activation of RNase L in the early stage of antiviral response [12]. The MX1(A) protein has also been shown to be involved in HCV induced stress granules formation that regulate HCV replication through virus assembly and egress [13].…”

Section: Resultsmentioning

confidence: 99%

The spliceosome factor SART1 exerts its anti-HCV action through mRNA splicing

Lin

Zhu

Hong

et al. 2015

Journal of Hepatology

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Background/Aims The broadly antiviral cytokine interferon-α (IFNα)’s mechanisms of action against HCV infection are not well understood. We previously identified SART1, a host protein involved in RNA splicing and pre-mRNA processing, as a regulator of IFN’s antiviral effects. We hypothesized that SART1 regulates antiviral effector genes (IEGs) through mRNA processing and splicing. Methods We performed siRNA knockdown in Huh7.5.1 cells and mRNA-seq with or without IFN treatment. Selected gene mRNA variants and their proteins, together with HCV replication, were monitored by qRT-PCR and Western blot in HCV OR6 replicon cells and the JFH1 HCV infectious model. Results we identified 419 genes with greater than 2-fold expression difference between Neg siRNA and SART1 siRNA treated cells in the presence or absence of IFN. Bioinformatic analysis identified at least 10 functional pathways. SART1 knockdown reduced classical ISG mRNA transcription including MX1 and OAS3. However, SART1 did not affect Jak-STAT pathway gene mRNA expression and IFN stimulated response element (ISRE) signaling. We identified alternative mRNA splicing events for several genes, including EIF4G3, GORASP2, ZFAND6, and RAB6A that contribute to their antiviral effects. EIF4G3 and GORASP2 were also confirmed to have anti-HCV effect. Conclusions The spliceosome factor SART1 is not IFN-inducible but is an IFN effector gene. SART1 exerts its anti-HCV action through direct transcriptional regulation for some ISGs and alternative splicing for others, including EIF4G3, GORASP2. SART1 does not have effects on IFN receptor or canonical signal transduction components. Thus, SART1 regulates ISGs using a novel, non-classical mechanism.

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Section: Resultsmentioning

confidence: 99%

The spliceosome factor SART1 exerts its anti-HCV action through mRNA splicing

Lin

Zhu

Hong

et al. 2015

Journal of Hepatology

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“…The Neandertal-introgressed allele encodes a protein variant (p46) that is associated with higher enzymatic activity [36]. The adaptive potential of this variant is supported by the observation that this variant (or other variants in strong LD with it) was shown to be associated with: (1) reduced infection and replication rates of West Nile virus ([38], but see [39]); (2) improved resistance to hepatitis C virus (HCV) infection [40, 41]; and (3) variable symptomology of tick-borne encephalitis (TBE) virus-induced disease (homozygous individuals for the Neandertal haplotype show the most severe symptoms of TBE). Strikingly, West Nile, hepatitis C, and TBE are all members of the Flaviviridae family, suggesting that Flaviviruses might have been the main drivers of selection in OAS1 .…”

Section: Discussionmentioning

confidence: 99%

Adaptively introgressed Neandertal haplotype at the OAS locus functionally impacts innate immune responses in humans

et al. 2016

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BackgroundThe 2’-5’ oligoadenylate synthetase (OAS) locus encodes for three OAS enzymes (OAS1-3) involved in innate immune response. This region harbors high amounts of Neandertal ancestry in non-African populations; yet, strong evidence of positive selection in the OAS region is still lacking.ResultsHere we used a broad array of selection tests in concert with neutral coalescent simulations to demonstrate a signal of adaptive introgression at the OAS locus. Furthermore, we characterized the functional consequences of the Neandertal haplotype in the transcriptional regulation of OAS genes at baseline and infected conditions. We found that cells from people with the Neandertal-like haplotype express lower levels of OAS3 upon infection, as well as distinct isoforms of OAS1 and OAS2.ConclusionsWe present evidence that a Neandertal haplotype at the OAS locus was subjected to positive selection in the human population. This haplotype is significantly associated with functional consequences at the level of transcriptional regulation of innate immune responses. Notably, we suggest that the Neandertal-introgressed haplotype likely reintroduced an ancestral splice variant of OAS1 encoding a more active protein, suggesting that adaptive introgression occurred as a means to resurrect adaptive variation that had been lost outside Africa.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-1098-6) contains supplementary material, which is available to authorized users.

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“…In Hepatitis C virus (HCV) patients it was found that patients with AA in rs10774671 were non-responders to interferon treatment and they had a progressive HCV disease [25]. When overexpressing the individual OAS proteins in human hepatoma Huh7 cells, OAS1 p46 as well as OAS3 p100 could inhibit HCV replication, whereas the OAS1 isoforms p42, p48 and p52 and the OAS2 isoforms p69 and p71 could not [26]. This suggests that expression of p46 caused by the G allele of the rs10774671 SNP is protective of HCV infection, or the A allele could be a risk factor.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial localization of the OAS1 p46 isoform associated with a common single nucleotide polymorphism

et al. 2014

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BackgroundThe expression of 2′-5′-Oligoadenylate synthetases (OASs) is induced by type 1 Interferons (IFNs) in response to viral infection. The OAS proteins have a unique ability to produce 2′-5′ Oligoadenylates, which bind and activate the ribonuclease RNase L. The RNase L degrades cellular RNAs which in turn inhibits protein translation and induces apoptosis. Several single nucleotide polymorphisms (SNPs) in the OAS1 gene have been associated with disease. We have investigated the functional effect of two common SNPs in the OAS1 gene. The SNP rs10774671 affects splicing to one of the exons in the OAS1 gene giving rise to differential expression of the OAS1 isoforms, and the SNP rs1131454 (former rs3741981) resides in exon 3 giving rise to OAS1 isoforms with either a Glycine or a Serine at position 162 in the core OAS unit.ResultsWe have used three human cell lines with different genotypes in the OAS1 SNP rs10774671, HeLa cells with the AA genotype, HT1080 cells with AG, and Daudi cells with GG. The main OAS1 isoform expressed in Daudi and HT1080 cells was p46, and the main OAS1 isoform expressed in HeLa cells was p42. In addition, low levels of the OAS1 p52 mRNA was detected in HeLa cells and p48 mRNA in Daudi cells, and trace amounts of p44a mRNA were detected in the three cell lines treated with type 1 interferon. We show that the OAS1 p46 isoform was localized in the mitochondria in Daudi cells, whereas the OAS1 isoforms in HeLa cells were primarily localized in cytoplasmic vacuoles/lysosomes. By using recombinantly expressed OAS1 mutant proteins, we found that the OAS1 SNP rs1131454 (former rs3741981) did not affect the enzymatic OAS1 activity.ConclusionsThe SNP rs10774671 determines differential expression of the OAS1 isoforms. In Daudi and HT1080 cells the p46 isoform is the most abundantly expressed isoform associated with the G allele, whereas in HeLa cells the most abundantly expressed isoform is p42 associated with the A allele. The SNP rs1131454 (former rs3741981) does not interfere with OAS1 enzyme activity. The OAS1 p46 isoform localizes to the mitochondria, therefore a full 2-5A system can now be found in the mitochondria.

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The ribonuclease l‐dependent antiviral roles of human 2′,5′‐oligoadenylate synthetase family members against hepatitis C virus

Cited by 51 publications

References 31 publications

The spliceosome factor SART1 exerts its anti-HCV action through mRNA splicing

The spliceosome factor SART1 exerts its anti-HCV action through mRNA splicing

Adaptively introgressed Neandertal haplotype at the OAS locus functionally impacts innate immune responses in humans

Mitochondrial localization of the OAS1 p46 isoform associated with a common single nucleotide polymorphism

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