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Activation of ERAD Pathway by Human Hepatitis B Virus Modulates Viral and Subviral Particle Production
Hepatitis B virus (HBV) belongs to the Hepadnaviridae family of enveloped DNA viruses. It was previously shown that HBV can induce endoplasmic reticulum (ER) stress and activate the IRE1-XBP1 pathway of the unfolded protein response (UPR), through the expression of the viral regulatory protein X (HB...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3312915/ https://www.ncbi.nlm.nih.gov/pubmed/22461906 http://dx.doi.org/10.1371/journal.pone.0034169 |
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author | Lazar, Catalin Macovei, Alina Petrescu, Stefana Branza-Nichita, Norica |
author_facet | Lazar, Catalin Macovei, Alina Petrescu, Stefana Branza-Nichita, Norica |
author_sort | Lazar, Catalin |
collection | PubMed |
description | Hepatitis B virus (HBV) belongs to the Hepadnaviridae family of enveloped DNA viruses. It was previously shown that HBV can induce endoplasmic reticulum (ER) stress and activate the IRE1-XBP1 pathway of the unfolded protein response (UPR), through the expression of the viral regulatory protein X (HBx). However, it remained obscure whether or not this activation had any functional consequences on the target genes of the UPR pathway. Of these targets, the ER degradation-enhancing, mannosidase-like proteins (EDEMs) are thought to play an important role in relieving the ER stress during UPR, by recognizing terminally misfolded glycoproteins and delivering them to the ER-associated degradation (ERAD). In this study, we investigated the role of EDEMs in the HBV life-cycle. We found that synthesis of EDEMs (EDEM1 and its homologues, EDEM2 and EDEM3) is significantly up-regulated in cells with persistent or transient HBV replication. Co-expression of the wild-type HBV envelope proteins with EDEM1 resulted in their massive degradation, a process reversed by EDEM1 silencing. Surprisingly, the autophagy/lysosomes, rather than the proteasome were involved in disposal of the HBV envelope proteins. Importantly, inhibition of the endogenous EDEM1 expression in HBV replicating cells significantly increased secretion of both, enveloped virus and subviral particles. This is the first report showing that HBV activates the ERAD pathway, which, in turn, reduces the amount of envelope proteins, possibly as a mechanism to control the level of virus particles in infected cells and facilitate the establishment of chronic infections. |
format | Online Article Text |
id | pubmed-3312915 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-33129152012-03-29 Activation of ERAD Pathway by Human Hepatitis B Virus Modulates Viral and Subviral Particle Production Lazar, Catalin Macovei, Alina Petrescu, Stefana Branza-Nichita, Norica PLoS One Research Article Hepatitis B virus (HBV) belongs to the Hepadnaviridae family of enveloped DNA viruses. It was previously shown that HBV can induce endoplasmic reticulum (ER) stress and activate the IRE1-XBP1 pathway of the unfolded protein response (UPR), through the expression of the viral regulatory protein X (HBx). However, it remained obscure whether or not this activation had any functional consequences on the target genes of the UPR pathway. Of these targets, the ER degradation-enhancing, mannosidase-like proteins (EDEMs) are thought to play an important role in relieving the ER stress during UPR, by recognizing terminally misfolded glycoproteins and delivering them to the ER-associated degradation (ERAD). In this study, we investigated the role of EDEMs in the HBV life-cycle. We found that synthesis of EDEMs (EDEM1 and its homologues, EDEM2 and EDEM3) is significantly up-regulated in cells with persistent or transient HBV replication. Co-expression of the wild-type HBV envelope proteins with EDEM1 resulted in their massive degradation, a process reversed by EDEM1 silencing. Surprisingly, the autophagy/lysosomes, rather than the proteasome were involved in disposal of the HBV envelope proteins. Importantly, inhibition of the endogenous EDEM1 expression in HBV replicating cells significantly increased secretion of both, enveloped virus and subviral particles. This is the first report showing that HBV activates the ERAD pathway, which, in turn, reduces the amount of envelope proteins, possibly as a mechanism to control the level of virus particles in infected cells and facilitate the establishment of chronic infections. Public Library of Science 2012-03-26 /pmc/articles/PMC3312915/ /pubmed/22461906 http://dx.doi.org/10.1371/journal.pone.0034169 Text en Lazar et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Lazar, Catalin Macovei, Alina Petrescu, Stefana Branza-Nichita, Norica Activation of ERAD Pathway by Human Hepatitis B Virus Modulates Viral and Subviral Particle Production |
title | Activation of ERAD Pathway by Human Hepatitis B Virus Modulates Viral and Subviral Particle Production |
title_full | Activation of ERAD Pathway by Human Hepatitis B Virus Modulates Viral and Subviral Particle Production |
title_fullStr | Activation of ERAD Pathway by Human Hepatitis B Virus Modulates Viral and Subviral Particle Production |
title_full_unstemmed | Activation of ERAD Pathway by Human Hepatitis B Virus Modulates Viral and Subviral Particle Production |
title_short | Activation of ERAD Pathway by Human Hepatitis B Virus Modulates Viral and Subviral Particle Production |
title_sort | activation of erad pathway by human hepatitis b virus modulates viral and subviral particle production |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3312915/ https://www.ncbi.nlm.nih.gov/pubmed/22461906 http://dx.doi.org/10.1371/journal.pone.0034169 |
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