Hepatitis C virus induces E6AP-dependent degradation of the retinoblastoma protein.

Hepatitis C virus (HCV) is a positive-strand RNA virus that frequently causes persistent infections and is uniquely associated with the development of hepatocellular carcinoma. While the mechanism(s) by which the virus promotes cancer are poorly defined, previous studies indicate that the HCV RNA-de...

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Autores principales:	Tsubasa Munakata, Yuqiong Liang, Seungtaek Kim, David R McGivern, Jon Huibregtse, Akio Nomoto, Stanley M Lemon
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2007
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/0568ef9e704b4989a0d3db167ecb1237
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spelling	oai:doaj.org-article:0568ef9e704b4989a0d3db167ecb12372021-11-25T05:46:24ZHepatitis C virus induces E6AP-dependent degradation of the retinoblastoma protein.1553-73661553-737410.1371/journal.ppat.0030139https://doaj.org/article/0568ef9e704b4989a0d3db167ecb12372007-09-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.0030139https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Hepatitis C virus (HCV) is a positive-strand RNA virus that frequently causes persistent infections and is uniquely associated with the development of hepatocellular carcinoma. While the mechanism(s) by which the virus promotes cancer are poorly defined, previous studies indicate that the HCV RNA-dependent RNA polymerase, nonstructural protein 5B (NS5B), forms a complex with the retinoblastoma tumor suppressor protein (pRb), targeting it for degradation, activating E2F-responsive promoters, and stimulating cellular proliferation. Here, we describe the mechanism underlying pRb regulation by HCV and its relevance to HCV infection. We show that the abundance of pRb is strongly downregulated, and its normal nuclear localization altered to include a major cytoplasmic component, following infection of cultured hepatoma cells with either genotype 1a or 2a HCV. We further demonstrate that this is due to NS5B-dependent ubiquitination of pRb and its subsequent degradation via the proteasome. The NS5B-dependent ubiquitination of pRb requires the ubiquitin ligase activity of E6-associated protein (E6AP), as pRb abundance was restored by siRNA knockdown of E6AP or overexpression of a dominant-negative E6AP mutant in cells containing HCV RNA replicons. E6AP also forms a complex with pRb in an NS5B-dependent manner. These findings suggest a novel mechanism for the regulation of pRb in which the HCV NS5B protein traps pRb in the cytoplasm, and subsequently recruits E6AP to this complex in a process that leads to the ubiquitination of pRb. The disruption of pRb/E2F regulatory pathways in cells infected with HCV is likely to promote hepatocellular proliferation and chromosomal instability, factors important for the development of liver cancer.Tsubasa MunakataYuqiong LiangSeungtaek KimDavid R McGivernJon HuibregtseAkio NomotoStanley M LemonPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 3, Iss 9, Pp 1335-1347 (2007)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Tsubasa Munakata Yuqiong Liang Seungtaek Kim David R McGivern Jon Huibregtse Akio Nomoto Stanley M Lemon Hepatitis C virus induces E6AP-dependent degradation of the retinoblastoma protein.
description	Hepatitis C virus (HCV) is a positive-strand RNA virus that frequently causes persistent infections and is uniquely associated with the development of hepatocellular carcinoma. While the mechanism(s) by which the virus promotes cancer are poorly defined, previous studies indicate that the HCV RNA-dependent RNA polymerase, nonstructural protein 5B (NS5B), forms a complex with the retinoblastoma tumor suppressor protein (pRb), targeting it for degradation, activating E2F-responsive promoters, and stimulating cellular proliferation. Here, we describe the mechanism underlying pRb regulation by HCV and its relevance to HCV infection. We show that the abundance of pRb is strongly downregulated, and its normal nuclear localization altered to include a major cytoplasmic component, following infection of cultured hepatoma cells with either genotype 1a or 2a HCV. We further demonstrate that this is due to NS5B-dependent ubiquitination of pRb and its subsequent degradation via the proteasome. The NS5B-dependent ubiquitination of pRb requires the ubiquitin ligase activity of E6-associated protein (E6AP), as pRb abundance was restored by siRNA knockdown of E6AP or overexpression of a dominant-negative E6AP mutant in cells containing HCV RNA replicons. E6AP also forms a complex with pRb in an NS5B-dependent manner. These findings suggest a novel mechanism for the regulation of pRb in which the HCV NS5B protein traps pRb in the cytoplasm, and subsequently recruits E6AP to this complex in a process that leads to the ubiquitination of pRb. The disruption of pRb/E2F regulatory pathways in cells infected with HCV is likely to promote hepatocellular proliferation and chromosomal instability, factors important for the development of liver cancer.
format	article
author	Tsubasa Munakata Yuqiong Liang Seungtaek Kim David R McGivern Jon Huibregtse Akio Nomoto Stanley M Lemon
author_facet	Tsubasa Munakata Yuqiong Liang Seungtaek Kim David R McGivern Jon Huibregtse Akio Nomoto Stanley M Lemon
author_sort	Tsubasa Munakata
title	Hepatitis C virus induces E6AP-dependent degradation of the retinoblastoma protein.
title_short	Hepatitis C virus induces E6AP-dependent degradation of the retinoblastoma protein.
title_full	Hepatitis C virus induces E6AP-dependent degradation of the retinoblastoma protein.
title_fullStr	Hepatitis C virus induces E6AP-dependent degradation of the retinoblastoma protein.
title_full_unstemmed	Hepatitis C virus induces E6AP-dependent degradation of the retinoblastoma protein.
title_sort	hepatitis c virus induces e6ap-dependent degradation of the retinoblastoma protein.
publisher	Public Library of Science (PLoS)
publishDate	2007
url	https://doaj.org/article/0568ef9e704b4989a0d3db167ecb1237
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Hepatitis C virus induces E6AP-dependent degradation of the retinoblastoma protein.

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