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The Epigenetic Controller Lysine-Specific Demethylase 1 (LSD1) Regulates the Outcome of Hepatitis C Viral Infection

Hepatitis C virus (HCV) alters gene expression epigenetically to rearrange the cellular microenvironment in a beneficial way for its life cycle. The host epigenetic changes induced by HCV lead to metabolic dysfunction and malignant transformation. Lysine-specific demethylase 1 (LSD1) is an epigeneti...

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Autores principales: Papadopoulou, Georgia, Petroulia, Stavroula, Karamichali, Eirini, Dimitriadis, Alexios, Marousis, Dimitrios, Ioannidou, Elisavet, Papazafiri, Panagiota, Koskinas, John, Foka, Pelagia, Georgopoulou, Urania
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10648375/
https://www.ncbi.nlm.nih.gov/pubmed/37947646
http://dx.doi.org/10.3390/cells12212568
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author Papadopoulou, Georgia
Petroulia, Stavroula
Karamichali, Eirini
Dimitriadis, Alexios
Marousis, Dimitrios
Ioannidou, Elisavet
Papazafiri, Panagiota
Koskinas, John
Foka, Pelagia
Georgopoulou, Urania
author_facet Papadopoulou, Georgia
Petroulia, Stavroula
Karamichali, Eirini
Dimitriadis, Alexios
Marousis, Dimitrios
Ioannidou, Elisavet
Papazafiri, Panagiota
Koskinas, John
Foka, Pelagia
Georgopoulou, Urania
author_sort Papadopoulou, Georgia
collection PubMed
description Hepatitis C virus (HCV) alters gene expression epigenetically to rearrange the cellular microenvironment in a beneficial way for its life cycle. The host epigenetic changes induced by HCV lead to metabolic dysfunction and malignant transformation. Lysine-specific demethylase 1 (LSD1) is an epigenetic controller of critical cellular functions that are essential for HCV propagation. We investigated the putative role of LSD1 in the establishment of HCV infection using genetic engineering and pharmacological inhibition to alter endogenous LSD1 levels. We demonstrated for the first time that HCV replication was inhibited in LSD1-overexpressing cells, while specific HCV proteins differentially fine-tuned endogenous LSD1 expression levels. Electroporation of the full-length HCV genome and subgenomic replicons in LSD1 overexpression enhanced translation and partially restored HCV replication, suggesting that HCV might be inhibited by LSD1 during the early steps of infection. Conversely, the inhibition of LSD1, followed by HCV infection in vitro, increased viral replication. LSD1 was shown to participate in an intriguing antiviral mechanism, where it activates endolysosomal interferon-induced transmembrane protein 3 (IFITM3) via demethylation, leading endocytosed HCV virions to degradation. Our study proposes that HCV-mediated LSD1 oscillations over countless viral life cycles throughout chronic HCV infection may promote epigenetic changes related to HCV-induced hepatocarcinogenesis.
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spelling pubmed-106483752023-11-03 The Epigenetic Controller Lysine-Specific Demethylase 1 (LSD1) Regulates the Outcome of Hepatitis C Viral Infection Papadopoulou, Georgia Petroulia, Stavroula Karamichali, Eirini Dimitriadis, Alexios Marousis, Dimitrios Ioannidou, Elisavet Papazafiri, Panagiota Koskinas, John Foka, Pelagia Georgopoulou, Urania Cells Article Hepatitis C virus (HCV) alters gene expression epigenetically to rearrange the cellular microenvironment in a beneficial way for its life cycle. The host epigenetic changes induced by HCV lead to metabolic dysfunction and malignant transformation. Lysine-specific demethylase 1 (LSD1) is an epigenetic controller of critical cellular functions that are essential for HCV propagation. We investigated the putative role of LSD1 in the establishment of HCV infection using genetic engineering and pharmacological inhibition to alter endogenous LSD1 levels. We demonstrated for the first time that HCV replication was inhibited in LSD1-overexpressing cells, while specific HCV proteins differentially fine-tuned endogenous LSD1 expression levels. Electroporation of the full-length HCV genome and subgenomic replicons in LSD1 overexpression enhanced translation and partially restored HCV replication, suggesting that HCV might be inhibited by LSD1 during the early steps of infection. Conversely, the inhibition of LSD1, followed by HCV infection in vitro, increased viral replication. LSD1 was shown to participate in an intriguing antiviral mechanism, where it activates endolysosomal interferon-induced transmembrane protein 3 (IFITM3) via demethylation, leading endocytosed HCV virions to degradation. Our study proposes that HCV-mediated LSD1 oscillations over countless viral life cycles throughout chronic HCV infection may promote epigenetic changes related to HCV-induced hepatocarcinogenesis. MDPI 2023-11-03 /pmc/articles/PMC10648375/ /pubmed/37947646 http://dx.doi.org/10.3390/cells12212568 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Papadopoulou, Georgia
Petroulia, Stavroula
Karamichali, Eirini
Dimitriadis, Alexios
Marousis, Dimitrios
Ioannidou, Elisavet
Papazafiri, Panagiota
Koskinas, John
Foka, Pelagia
Georgopoulou, Urania
The Epigenetic Controller Lysine-Specific Demethylase 1 (LSD1) Regulates the Outcome of Hepatitis C Viral Infection
title The Epigenetic Controller Lysine-Specific Demethylase 1 (LSD1) Regulates the Outcome of Hepatitis C Viral Infection
title_full The Epigenetic Controller Lysine-Specific Demethylase 1 (LSD1) Regulates the Outcome of Hepatitis C Viral Infection
title_fullStr The Epigenetic Controller Lysine-Specific Demethylase 1 (LSD1) Regulates the Outcome of Hepatitis C Viral Infection
title_full_unstemmed The Epigenetic Controller Lysine-Specific Demethylase 1 (LSD1) Regulates the Outcome of Hepatitis C Viral Infection
title_short The Epigenetic Controller Lysine-Specific Demethylase 1 (LSD1) Regulates the Outcome of Hepatitis C Viral Infection
title_sort epigenetic controller lysine-specific demethylase 1 (lsd1) regulates the outcome of hepatitis c viral infection
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10648375/
https://www.ncbi.nlm.nih.gov/pubmed/37947646
http://dx.doi.org/10.3390/cells12212568
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