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The unique proteasomal processing of viral ORF1 drives HEV-induced liver fibrosis

ABSTRACT: The unique proteasomal processing of viral ORF1 drives HEV-induced liver fibrosis

PROVIDER: PRJNA1055932 | ENA |

REPOSITORIES: ENA

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The unique proteasomal processing of viral ORF1 drives HEV-induced liver fibrosis

Project description:Hepatitis E virus (HEV) is a globally prevalent pathogen that causes 20 million infections and 60,000 fatalities annually, endangering particularly pregnant women and immunosuppressed individuals. Liver cirrhosis, which results from advanced fibrosis, is the primary symptom and leading mortality cause in chronic hepatitis E patients. However, the causation and process of liver fibrosis triggered by chronic HEV infection remain poorly understood. Here, we unexpectedly discovered that the viral multiple-domain replicase (ORF1) undergoes unique ubiquitin-proteasomal processing in HEV replicon hepatocytes, HEV-infected gerbil livers, and HEV-infected patient livers, which follows a CHIP-mediated K48 ubiquitination and produces the HEV-Derived Smad Activator (HDSA). Lacking putative helicase and RNA polymerase domains, this enriched viral polypeptide in hepatocytes and gerbil livers is non-HSP90-bound, stable, and exhibits exclusively nuclear localization. Surprisingly, HDSA markedly potentiates the fibrogenic TGF-β/Smad pathway in livers by facilitating promoter binding and coactivator recruitment of SMAD3, leading to profound liver fibrotic symptoms and damage. Thus, we have identified the first viral protein derived from the unique proteasomal processing of the host, defined its notable role in liver fibrosis, and highlighted the nature of complex host-HEV interactions that drives HEV pathogenesis.

2024-08-01 | GSE251924 | GEO

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Project description:We aimed to identify interferon (IFN)-regulated genes that are differentially expressed during chronic HEV infection in human hepatocytes, the main site of HEV replication, using HepaRG cells. We have performed a preliminary screen using whole-cell RNA extracts prepared from HepaRG mock-infected or infected cells to determine whether HEV was able to trigger an IFN response. Different multiplicities of infection (MOI) (10 and 100 genome equivalent (GE)/cell) and time points (D+7, D+14, D+26, D+40, D+72 and D+100) were analyzed using the PCR array. We have also treated HepaRG cells after overnight treatment with IFN-β to confirm the ability of HepaRG to respond to IFN-I treatment.

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Unique expression, processing regulation, and regulatory network of peach (Prunus persica) miRNAs

Project description:We performed small RNA deep sequencing and identified 47 peach-specific and 47 known miRNAs or families with distinct expression patterns. Together, the identified miRNAs targeted 80 genes, many of which have not been reported previously. Like the model plant systems, peach has two of the three conserved trans-acting siRNA biogenesis pathways with similar mechanistic features and target specificity. Unique to peach, three of the miRNAs collectively target 49 MYBs, 19 of which are known to regulate phenylpropanoid metabolism, a key pathway associated with stone hardening and fruit color development, highlighting a critical role of miRNAs in regulation of peach fruit development and ripening. We also found that the majority of the miRNAs were differentially regulated in different tissues, in part due to differential processing of miRNA precursors. Up to 16% of the peach-specific miRNAs were differentially processed from their precursors in a tissue specific fashion, which has been rarely observed in plant cells. The miRNA precursor processing activity appeared not to be coupled with its transcriptional activity but rather acted independently in peach. Collectively, the data characterizes the unique expression pattern and processing regulation of peach miRNAs and demonstrates the presence of a complex, multi-level miRNA regulatory network capable of targeting a wide variety of biological functions, including phenylpropanoid pathways which play a multifaceted spatial-temporal role in peach fruit development. Identification of peach miRNAs and their targets from four different tissues

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