Hepatitis E Virus Replication Requires an Active Ubiquitin-Proteasome System

Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.
Journal of Virology (Impact Factor: 4.44). 03/2012; 86(10):5948-52. DOI: 10.1128/JVI.07039-11
Source: PubMed


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.

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    • "A previous study showed that the inhibition of UPS impairs the viral infection cycle (Raaben et al., 2010). For instance, MG132 affects hepatitis E virus replication likely through the inhibition of viral transcription and/or translation without a significant effect on cellular translation (Karpe and Meng, 2012). Wang et al. (2011) demonstrated that cellular inhibitor of apoptosis protein 2 (cIAP2) can significantly reduce the levels of hepatitis B virus DNA replication via acceleration of the UPS-mediated decay of the polymerase. "
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    ABSTRACT: Porcine circovirus type 2 (PCV2) is the primary causative agent of porcine circovirus-associated diseases (PCVAD). It has been shown that the ubiquitin-proteasome system (UPS) is correlated with viral infection, but its role in PCV2 replication remains unknown. In the present study, we explored the interplay between PCV2 replication and the UPS in PK15 cells and found that treatment with a proteasome inhibitor (MG132 and lactacystin) significantly decreased the PCV2 titer at the early infection stage. We further revealed that inhibition of the UPS did not affect virus entry but decreased viral protein expression and RNA transcription potentially in a cell cycle-dependent manner. PCV2 infection has little effect on the chymotrypsin-like activity, and the gene-silencing of ubiquitin reduced the PCV2 titer, which indicates that the effective replication of PCV2 may be related to protein ubiquitination. Taken together, our data suggested that PCV2 replication requires the UPS machinery, which may represent a potential antiviral target against PCV2.
    Preview · Article · May 2014 · Virology
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    • "The specific roles of Zn 2+ require further investigation. UPS has been demonstrated to be important for the replication of several viruses, and many viruses have evolved to hijack host cellular proteasome to facilitate their effective infection (Kanlaya et al., 2010; Karpe and Meng, 2012; Klinger and Schubert, 2005; Neznanov et al., 2008; Raaben et al., 2010; Satheshkumar et al., 2009; Si et al., 2008; Teale et al., 2009; Thomas et al., 1999; Widjaja et al., 2010). HSV ICP0 with RING-finger domain acted as ubiquitin E3 ligase and induced degradation of cellular component proteins, such as PML and Sp100 (Boutell et al., 2002; Parkinson and Everett, 2000). "
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    ABSTRACT: Pyrithione (PT), known as a zinc ionophore, is effective against several pathogens from the Streptococcus and Staphylococcus genera. The antiviral activity of PT was also reported against a number of RNA viruses. In this paper, we showed that PT could effectively inhibit herpes simplex virus types 1 and 2 (HSV-1 and HSV-2). PT inhibited HSV late gene (Glycoprotein D, gD) expression and the production of viral progeny, and this action was dependent on Zn(2+). Further studies showed that PT suppressed the expression of HSV immediate early (IE) gene, the infected cell polypeptide 4 (ICP4), but had less effect on another regulatory IE protein, ICP0. It was found that PT treatment could interfere with cellular ubiquitin-proteasome system (UPS), leading to the inhibition of HSV-2-induced IκB-α degradation to inhibit NF-κB activation and enhanced promyelocytic leukemia protein (PML) stability in nucleus. However, PT did not show direct inhibition of 26S proteasome activity. Instead, it induced Zn(2+) influx, which facilitated the dysregulation of UPS and the accumulation of intracellular ubiquitin-conjugates. UPS inhibition by PT caused disruption of IκB-α degradation and NF-κB activation thus leading to marked reduction of viral titration.
    Full-text · Article · Jul 2013 · Antiviral research
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    • "ORF2 overlaps ORF3 but neither overlaps ORF1 (Huang et al., 2007). HEV ORF1 encodes non-structural proteins like the RNA-dependent RNA polymerase, methyltransferase, RNA helicase and cysteine protease (Karpe and Meng, 2012; Koonin et al., 1992). ORF2 encodes the capsid protein, while ORF3 encodes a multifunctional small phosphoprotein (Chandra et al., 2011; Kenney et al., 2012; Tam et al., 1991; Zafrullah et al., 1997). "
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    ABSTRACT: Swine hepatitis E virus (HEV) is a zoonotic virus and pigs are considered as an important reservoir. Swine HEV infection is widespread and most pig herds are infected. Humans can be infected with swine HEV via consumption of undercooked pork or through direct contact with infected pigs. To minimize the risk of zoonotic transmission, sensitive tools to assess the HEV infection status of pigs and pork products are needed. The objective of this study was to develop a fluorescent microbead-based immunoassay (FMIA) for the detection of IgG antibodies against swine HEV and compare it to an in house enzyme-linked immunoassay (ELISA). Three sets of samples were utilized: (A) samples from pigs infected experimentally with different strains of HEV (positive controls, n=72), (B) samples from known HEV-negative pigs (negative controls, n=62) and (C) samples from pigs of unknown HEV infection status (n=182). All samples were tested by both ELISA and FMIA. The results on the experimental samples with known HEV exposure indicate that both assays have a specificity of 100% while the sensitivity ranges from 84.6% (ELISA) to 92.3% (FMIA). The overall prevalence of HEV IgG antibodies in field samples from pigs with unknown HEV exposure was 21.9% (40/182) for the ELISA and 21.4% (39/182) for the FMIA. The two assays had an almost perfect overall agreement (Kappa=0.92).
    Full-text · Article · Jun 2013 · Journal of virological methods
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