Cargando…
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...
Autores principales: | , , , , , , , , , |
---|---|
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 |
_version_ | 1785135325883924480 |
---|---|
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. |
format | Online Article Text |
id | pubmed-10648375 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT papadopoulougeorgia theepigeneticcontrollerlysinespecificdemethylase1lsd1regulatestheoutcomeofhepatitiscviralinfection AT petrouliastavroula theepigeneticcontrollerlysinespecificdemethylase1lsd1regulatestheoutcomeofhepatitiscviralinfection AT karamichalieirini theepigeneticcontrollerlysinespecificdemethylase1lsd1regulatestheoutcomeofhepatitiscviralinfection AT dimitriadisalexios theepigeneticcontrollerlysinespecificdemethylase1lsd1regulatestheoutcomeofhepatitiscviralinfection AT marousisdimitrios theepigeneticcontrollerlysinespecificdemethylase1lsd1regulatestheoutcomeofhepatitiscviralinfection AT ioannidouelisavet theepigeneticcontrollerlysinespecificdemethylase1lsd1regulatestheoutcomeofhepatitiscviralinfection AT papazafiripanagiota theepigeneticcontrollerlysinespecificdemethylase1lsd1regulatestheoutcomeofhepatitiscviralinfection AT koskinasjohn theepigeneticcontrollerlysinespecificdemethylase1lsd1regulatestheoutcomeofhepatitiscviralinfection AT fokapelagia theepigeneticcontrollerlysinespecificdemethylase1lsd1regulatestheoutcomeofhepatitiscviralinfection AT georgopoulouurania theepigeneticcontrollerlysinespecificdemethylase1lsd1regulatestheoutcomeofhepatitiscviralinfection AT papadopoulougeorgia epigeneticcontrollerlysinespecificdemethylase1lsd1regulatestheoutcomeofhepatitiscviralinfection AT petrouliastavroula epigeneticcontrollerlysinespecificdemethylase1lsd1regulatestheoutcomeofhepatitiscviralinfection AT karamichalieirini epigeneticcontrollerlysinespecificdemethylase1lsd1regulatestheoutcomeofhepatitiscviralinfection AT dimitriadisalexios epigeneticcontrollerlysinespecificdemethylase1lsd1regulatestheoutcomeofhepatitiscviralinfection AT marousisdimitrios epigeneticcontrollerlysinespecificdemethylase1lsd1regulatestheoutcomeofhepatitiscviralinfection AT ioannidouelisavet epigeneticcontrollerlysinespecificdemethylase1lsd1regulatestheoutcomeofhepatitiscviralinfection AT papazafiripanagiota epigeneticcontrollerlysinespecificdemethylase1lsd1regulatestheoutcomeofhepatitiscviralinfection AT koskinasjohn epigeneticcontrollerlysinespecificdemethylase1lsd1regulatestheoutcomeofhepatitiscviralinfection AT fokapelagia epigeneticcontrollerlysinespecificdemethylase1lsd1regulatestheoutcomeofhepatitiscviralinfection AT georgopoulouurania epigeneticcontrollerlysinespecificdemethylase1lsd1regulatestheoutcomeofhepatitiscviralinfection |