Hepatitis E Virus Replication Requires an Active Ubiquitin-Proteasome System

ArticleinJournal of Virology 86(10):5948-52 · March 2012with23 Reads
DOI: 10.1128/JVI.07039-11 · Source: PubMed
Abstract
The mechanism of hepatitis E virus (HEV) replication remains largely unknown. Here we demonstrate that HEV replication requires an active ubiquitin-proteasome system and that proteasome inhibitors affect HEV replication, possibly by inhibition of viral transcription or/and translation without a significant effect on cellular translation. Overexpression of ubiquitin in inhibitor-treated cells partially reverses the inhibitor effect on HEV replication. The results suggest that HEV replication requires interactions with proteasome machinery, which could be a potential therapeutic target against HEV.
    • "The demonstration of alternating cycles of synthesis of negative-and positive-sense RNA in a cell culture system [47] provides a strong support to the mechanism described above. Furthermore, replication of HEV has been shown to depend on the presence of an active ubiquitin–proteasome system [48]. Thus, inhibitors of this system have been shown to reduce HEV replication without a significant effect on cellular translation; however, whether this effect is due to inhibition of viral transcription, translation, or both remains unclear. "
    [Show abstract] [Hide abstract] ABSTRACT: Infection with hepatitis E virus (HEV) is the most common cause of acute hepatitis worldwide. HEV exists mainly as non-enveloped virions with an approximately 7.2-kilobase long positive-stranded RNA genome. An enveloped form that circulates in the host has also been recently recognized. Originally believed to naturally infect only humans and possibly primates, HEV-like viruses are now known to infect several vertebrate animals, increasing the interest in this infection. This discovery, along with the development of replicons and in vitro infection systems, has improved our understanding about the virus and the pathogenesis of infection with it. Recent development of mouse models with chimeric livers that contain human hepatocytes provides a new avenue for further advancement of this knowledge. The diagnosis of HEV infection is based on the detection of one of viral constituents or of host antibodies against it. In this article, we review the current knowledge about the structure, genomic organization, taxonomy, genetic epidemiology, host specificity and replication of the human HEV and of various closely-related viruses that infect other animals. In addition, the models available for the study of HEV infection, the available information on the pathogenesis of disease caused by HEV infection and the techniques available for the diagnosis of this infection are also reviewed. An accompanying article discusses the epidemiology, clinical manifestations and prevention of this infection.
    Article · May 2016
    • "In cultured human hepatoma cells, pORF2 inhibits cellular NF-B activity by blocking ubiquitination mediated proteasomal degradation of IB (Surjit et al., 2012). Requirement of the functional UPS for optimum HEV replication is known (Karpe and Meng, 2012 ). HEV Methyltransferase-Y- Protease domain fusion protein has been shown to have in vitro deubiquitination activity (Karpe and Lole, 2011 ). "
    [Show abstract] [Hide abstract] ABSTRACT: Hepatitis E virus ORF1 encoded non-structural polyprotein (nsP) consist of multiple domains, namely: Methyltransferase, Y-domain, Protease, X-domain, Helicase and RNA dependent RNA polymerase. We have attempted to identify human liver cell proteins that are interacting with HEV ORF1 encoded functional domains by using Y2H screening. A total of 155 protein-protein interactions between HEV-ORF1 and human proteins were identified. Comparative analysis of the HEV-ORF1-Human interaction network with reconstructed human interactome showed that the cellular proteins interacting with HEV-ORF1 are central and interconnected. Enrichment analysis of Gene Ontology and cellular pathways showed that the viral proteins preferentially interacted with the proteins of metabolism and energy generation along with host immune response and ubiquitin proteasomal pathways. The mTOR and focal adhesion pathways were also targeted by the virus. These interactions suggest that HEV probably utilizes important proteins in carbohydrate metabolism, energy generation and iron homoeostasis in the host cells during its establishment.
    Full-text · Article · Dec 2015
    • "Treatment with the proteasome inhibitor MG132 has been shown to decrease the titer of porcine circovirus type 2 (PCV2) at an early stage of infection [22]. Treatment with MG132 has also been shown to decrease the activity of Renilla luciferase expressed from an HEV replicon [12]. However, our study raised concerns regarding the specificity of the effect of MG132 on HEV replication. "
    [Show abstract] [Hide abstract] ABSTRACT: The ubiquitin proteasome system plays important role in virus infection. A previous study showed that the proteasome inhibitor MG132 could potentially affect hepatitis E virus (HEV) replication. In this study, we found that MG132 could inhibit HEV and hepatitis C virus (HCV) replication-related luciferase activity in subgenomic models. Furthermore, treatment with MG132 in a HEV infectious model resulted in a dramatic reduction in the intracellular level of HEV RNA. Surprisingly, MG132 concurrently inhibited the expression of a luciferase gene used as a control as well as a wide range of host genes. Consistently, the total cellular RNA and protein content was concurrently reduced by MG132 treatment, suggesting a nonspecific antiviral effect.
    Full-text · Article · Dec 2014
Show more