C19orf66 is an interferon-induced inhibitor of HCV replication restricting formation of the viral replication organelle
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ABSTRACT:
PROVIDER: PRJNA609133 | ENA |
REPOSITORIES: ENA
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Project description:Hepatitis C virus (HCV) infection constitutes a global health problem with 71 million people currently chronically infected. Recent studies have reported that C19orf66 is expressed as an interferon (IFN)-stimulated gene; however, the intrinsic regulation of this gene within the liver as well as its antiviral effects against HCV remains elusive. In this study, we observed an upregulation of C19orf66 in vivo and ex vivo in response to HCV infection and to IFN therapy. Expression of C19orf66 restricted HCV infection, whereas CRIPSPR/Cas9 mediated knockout of C19orf66 attenuated IFN-mediated suppression of HCV replication. Co-immunoprecipitation followed by mass spectrometry identified a stress granule dominated interactome of C19orf66. Mechanistic studies revealed that C19orf66 expression impairs HCV-induced elevation of PI(4)P and alters the morphology of the viral replication organelle, designated membranous web, thus suppressing viral RNA replication. Collectively, our data suggest that C19orf66 contributes to the innate immune response against HCV in the liver.
2020-02-28 | GSE146075 | GEO
Project description:The liver-specific microRNA, miR-122, is an essential host factor for replication of hepatitis C virus (HCV), an important infectious cause of chronic liver disease and hepatocellular carcinoma. miR-122 stabilizes the positive-strand HCV RNA genome and promotes viral RNA synthesis by binding two closely spaced sites (S1 and S2) near the 5’ end of the genome in association with Ago2. Ago2 is essential for both host factor activities, but whether other host proteins are involved is unknown. Using a quantitative proteomics approach, we identified TNRC6A (GW182) and its paralogs (TNRC6B and TNRC6C), as functionally important components of the miR-122/Ago2 host factor complex binding HCV RNA. Depletion of any two TNRC6 proteins reduced HCV replication in Huh-7.5 cells,but did not reduce viral RNA stability or translational activity, but rather dampened miR-122 stimulation of viral RNA synthesis. However, TNRC6 depletion had no effect on replication of HCV in which S2 was mutated so that miR-122 binds only S1, whereas it significantly enhanced replication when S1 was mutated and only S2 bound by miR-122. Consistent with this, we found that TNRC6 proteins preferentially associate with the S1 site, and that the association of Ago2 with S2 is increased in TNRC6-depleted cells. Collectively, these data suggest a model in which TNRC6 proteins, which are known to interact with Ago2, preferentially direct the miR-122/Ago2 complex to S1 while restricting its association with S2, thereby fine tuning the spatial organization of miR-122/Ago2 complexes bound to the viral RNA.
2019-04-24 | PXD013054 | Pride
Project description:MX1 is a well-characterized interferon-induced antiviral gene. MX1 is activated by viral infection due to interferon production in cells. We treated non-permissive Huh7 cells and permissive HRP4 cells with interferon. We compared the expression of genes induced by interferon to determine host factors affecting HCV replication.
2013-07-03 | GSE31903 | GEO
Project description:MX1 is a well-characterized interferon-induced antiviral gene. MX1 is activated by viral infection due to interferon production in cells. We treated non-permissive Huh7 cells and permissive HRP4 cells with interferon. We compared the expression of genes induced by interferon to determine host factors affecting HCV replication. Huh7 cells and HRP4 cells were treated with 40U/ml interferon-α for 6h. RNA was extracted and hybridized on Affymetrix microarrays
2013-07-03 | E-GEOD-31903 | biostudies-arrayexpress
Project description: Not available
| S-EPMC8577994 | biostudies-literature
Project description:Double membrane vesicles (DMVs) are used as replication organelles by pathogenic RNA viruses such as hepatitis C virus (HCV) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Viral DMVs are morphologically analogous to DMVs formed during autophagy, and although the proteins required for DMV formation are extensively studied, the lipids driving their biogenesis are largely unknown. Here we show that production of the lipid phosphatidic acid (PA) by acylglycerolphosphate acyltransferase (AGPAT) 1 and 2 in the ER is important for DMV biogenesis in autophagy and viral replication. Using DMVs in HCV-replicating cells as model, we found that AGPATs are recruited to and critically contribute to viral replication in HCV and SARS-CoV-2 infected cells. AGPAT1/2 double knockout impaired HCV and SARS-CoV-2 induced DMV biogenesis as well as formation of autophagosomes. By using correlative light and electron microscopy, we observed the relocalisation of AGPAT proteins to viral DMVs. In addition, an intracellular PA sensor accumulated at DMV formation sites, consistent with elevated levels of PA in fractions of purified DMVs analyzed by lipidomics. Apart from AGPATs, PA is generated by alternative pathways via phosphotidylcholine (PC) and diacylglycerol (DAG). Pharmacological inhibition of these synthesis pathways also impaired HCV and SARS-CoV-2 replication. These data identify PA as an important lipid that is used in seemingly disparate biological processes, i.e. autophagy and replication organelle formation by diverse RNA viruses. In addition, our data argue that host-targeting therapy aiming at PA synthesis pathways might be suitable to control SARS-CoV-2 replication.
2022-01-24 | PXD029692 | Pride
Project description:Although treatment of chronic hepatitis C virus (HCV) infection with direct acting antivirals (DAAs) results in high rates of cure, liver fibrosis does not resolve immediately after HCV eradication. Resolution of fibrosis occurs in some, but not all patients, after HCV cure, and hepatic decompensation and hepatocellular carcinoma can still occur in patients with pre-existing cirrhosis. We hypothesized that evaluation of the host liver proteome in the context of HCV treatment would provide insight into how inflammatory and fibrinogenic pathways change upon HCV eradication. We evaluated the whole liver proteome and phosphoproteome using paired liver biopsies from 8 HCV-infected patients collected before or immediately after treatment with DAAs in clinical trials. We identify interferon stimulated proteins as the predominant pathways that decrease with HCV treatment, which is consistent with previous analyses of the liver transcriptome during DAA therapy. While there was no change in the proteome of pathways associated with liver fibrosis, we identified a decrease in the phosphoproteome signature for ERK1/ERK2 as a result of HCV treatment. Conclusion: There is a reduction in the endogenous interferon-mediated antiviral response and alterations in the phosphoproteome that may precede resolution of fibrosis in the liver immediately after treatment of HCV with DAAs.
2023-03-11 | PXD024846 | Pride
Project description:Viruses lack the basic machinery needed to replicate and therefore must hijack host metabolism to propagate. Virus-induced metabolic alterations have yet to be systematically studied in the context of the host transcriptional regulation, offering insight into host-pathogen metabolic interplay. In this work we identified Hepatitis C Virus (HCV)-responsive regulators by coupling system-wide metabolic flux analysis with targeted perturbation of nuclear receptors in primary human hepatocytes. We find HCV-induced up-regulation of glycolysis, ketogenesis and drug metabolism, controlled by activation of HNF4α, PPARα, FXR and PXR, respectively. Pharmaceutical inhibition of HNF4α reversed HCV-induced glycolysis, blocking viral replication while increasing apoptosis in infected cells showing a viral-induced dependence on glycolysis. In contrast, pharmaceutical inhibition of PPARα or FXR reversed HCV-induced ketogenesis, but increased viral replication demonstrating a unique host anti-viral response. Our results show that viral-induced changes to host metabolism can be detrimental to its lifecycle demonstrating a distinct biological complexity. In this dataset, we include the expression data obtained from primary human hepatocyte oxygenated co-cultures infected or not infected by HCV and human sanp frozen liver biopsys from HCV patients at earley stages.
2016-10-07 | GSE84587 | GEO
Project description:Tp80 is a novel antiviral compound. Antiviral mechanism of Tp80 is the inhibition of the viral genome replication through the recoverly of GPx2 expression downregulated by HCV infection. We used microarrays to evaluated the effect of Tp80 on the transcriptome of HCV replicon cells, compared with Non-infected host cells or non-treated HCV replicon cells.
2016-12-20 | GSE60488 | GEO
Project description:Purpose: The hepatoblasts are found to be optimal stage, compared with hepatic stem cells (hHpSCs) and mature hepatocytes (hHeps). To identify the cellular determinants that correlated with HCV infection during hES cells’ differentiation, transcriptome profiling of cells at hHpSC, hHB, PreHep and hHep stages were compared with RNA sequencing.Results: In general, the gene expression profile of cells at each stage clustered closer to the HCV infected cells at the same stages. The genes involved in regulation of liver development were up-regulated along with processes of maturation. Among the genes positively related to HCV replication, ABCB6, CEBPD, TNFRSF10C, GTF3A, HAS1, UBE2J1 were highly expressed in mature hHeps, while IGFBP6, SMAD6, ITGA7 etc. were highly expressed in progenitor hHB stage. Most of the 66 genes reported to be involved in HCV assembly and secretion remained unchanged, except CX3CL1 and PROX1 increased in mature hepatocyte and ARHGAF increased in rogenitors. Families of viral restriction factors reported involved in HCV infection were significantly enriched in hHeps. Conclusions: HCV does not change the transcription profile of induced cells and use different genes to support HCV replication in the cells from different stage. Low level of expression of viral restriction factors makes hHBs an optimal host for HCV infection.
2017-07-12 | GSE101133 | GEO