Activation of PERK-Nrf2 oncogenic signaling promotes Mdm2-mediated Rb degradation in persistently infected HCV culture

Abstract The mechanism of how chronic hepatitis C virus (HCV) infection leads to such a high rate of hepatocellular carcinoma (HCC) is unknown. We found that the PERK axis of endoplasmic reticulum (ER) stress elicited prominent nuclear translocation of Nrf2 in 100% of HCV infected hepatocytes. The s...

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Autores principales:	Yucel Aydin, Milad Chedid, Srinivas Chava, Donkita Danielle Williams, Shuanghu Liu, Curt H. Hagedorn, Suchitra Sumitran-Holgersson, Krzysztof Reiss, Krzysztof Moroz, Hua Lu, Luis A. Balart, Srikanta Dash
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1c273bda27a2435b98c2b3064a561524
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spelling	oai:doaj.org-article:1c273bda27a2435b98c2b3064a5615242021-12-02T12:30:28ZActivation of PERK-Nrf2 oncogenic signaling promotes Mdm2-mediated Rb degradation in persistently infected HCV culture10.1038/s41598-017-10087-62045-2322https://doaj.org/article/1c273bda27a2435b98c2b3064a5615242017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-10087-6https://doaj.org/toc/2045-2322Abstract The mechanism of how chronic hepatitis C virus (HCV) infection leads to such a high rate of hepatocellular carcinoma (HCC) is unknown. We found that the PERK axis of endoplasmic reticulum (ER) stress elicited prominent nuclear translocation of Nrf2 in 100% of HCV infected hepatocytes. The sustained nuclear translocation of Nrf2 in chronically infected culture induces Mdm2-mediated retinoblastoma protein (Rb) degradation. Silencing PERK and Nrf2 restored Mdm2-mediated Rb degradation, suggesting that sustained activation of PERK/Nrf2 axis creates oncogenic stress in chronically infected HCV culture model. The activation of Nrf2 and its nuclear translocation were prevented by ER-stress and PERK inhibitors, suggesting that PERK axis is involved in the sustained activation of Nrf2 signaling during chronic HCV infection. Furthermore, we show that HCV clearance induced by interferon-α based antiviral normalized the ER-stress response and prevented nuclear translocation of Nrf2, whereas HCV clearance by DAAs combination does neither. In conclusion, we report here a novel mechanism for how sustained activation of PERK axis of ER-stress during chronic HCV infection activates oncogenic Nrf2 signaling that promotes hepatocyte survival and oncogenesis by inducing Mdm2-mediated Rb degradation.Yucel AydinMilad ChedidSrinivas ChavaDonkita Danielle WilliamsShuanghu LiuCurt H. HagedornSuchitra Sumitran-HolgerssonKrzysztof ReissKrzysztof MorozHua LuLuis A. BalartSrikanta DashNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-15 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yucel Aydin Milad Chedid Srinivas Chava Donkita Danielle Williams Shuanghu Liu Curt H. Hagedorn Suchitra Sumitran-Holgersson Krzysztof Reiss Krzysztof Moroz Hua Lu Luis A. Balart Srikanta Dash Activation of PERK-Nrf2 oncogenic signaling promotes Mdm2-mediated Rb degradation in persistently infected HCV culture
description	Abstract The mechanism of how chronic hepatitis C virus (HCV) infection leads to such a high rate of hepatocellular carcinoma (HCC) is unknown. We found that the PERK axis of endoplasmic reticulum (ER) stress elicited prominent nuclear translocation of Nrf2 in 100% of HCV infected hepatocytes. The sustained nuclear translocation of Nrf2 in chronically infected culture induces Mdm2-mediated retinoblastoma protein (Rb) degradation. Silencing PERK and Nrf2 restored Mdm2-mediated Rb degradation, suggesting that sustained activation of PERK/Nrf2 axis creates oncogenic stress in chronically infected HCV culture model. The activation of Nrf2 and its nuclear translocation were prevented by ER-stress and PERK inhibitors, suggesting that PERK axis is involved in the sustained activation of Nrf2 signaling during chronic HCV infection. Furthermore, we show that HCV clearance induced by interferon-α based antiviral normalized the ER-stress response and prevented nuclear translocation of Nrf2, whereas HCV clearance by DAAs combination does neither. In conclusion, we report here a novel mechanism for how sustained activation of PERK axis of ER-stress during chronic HCV infection activates oncogenic Nrf2 signaling that promotes hepatocyte survival and oncogenesis by inducing Mdm2-mediated Rb degradation.
format	article
author	Yucel Aydin Milad Chedid Srinivas Chava Donkita Danielle Williams Shuanghu Liu Curt H. Hagedorn Suchitra Sumitran-Holgersson Krzysztof Reiss Krzysztof Moroz Hua Lu Luis A. Balart Srikanta Dash
author_facet	Yucel Aydin Milad Chedid Srinivas Chava Donkita Danielle Williams Shuanghu Liu Curt H. Hagedorn Suchitra Sumitran-Holgersson Krzysztof Reiss Krzysztof Moroz Hua Lu Luis A. Balart Srikanta Dash
author_sort	Yucel Aydin
title	Activation of PERK-Nrf2 oncogenic signaling promotes Mdm2-mediated Rb degradation in persistently infected HCV culture
title_short	Activation of PERK-Nrf2 oncogenic signaling promotes Mdm2-mediated Rb degradation in persistently infected HCV culture
title_full	Activation of PERK-Nrf2 oncogenic signaling promotes Mdm2-mediated Rb degradation in persistently infected HCV culture
title_fullStr	Activation of PERK-Nrf2 oncogenic signaling promotes Mdm2-mediated Rb degradation in persistently infected HCV culture
title_full_unstemmed	Activation of PERK-Nrf2 oncogenic signaling promotes Mdm2-mediated Rb degradation in persistently infected HCV culture
title_sort	activation of perk-nrf2 oncogenic signaling promotes mdm2-mediated rb degradation in persistently infected hcv culture
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/1c273bda27a2435b98c2b3064a561524
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Activation of PERK-Nrf2 oncogenic signaling promotes Mdm2-mediated Rb degradation in persistently infected HCV culture

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