期刊论文详细信息
PLoS Pathogens
Hepatitis C Virus Induces E6AP-Dependent Degradation of the Retinoblastoma Protein
Jon Huibregtse1  Tsubasa Munakata1  Stanley M Lemon1  Seungtaek Kim1  Akio Nomoto2  David R McGivern2  Yuqiong Liang3 
[1] Center for Hepatitis Research, University of Texas Medical Branch, Galveston, Texas, United States of America;Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America;Department of Microbiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
关键词: Hepatitis C virus;    Small interfering RNAs;    Ubiquitination;    Immunoblotting;    Immunoprecipitation;    Hepatocellular carcinoma;    Cytoplasm;    Ubiquitin ligases;   
DOI  :  10.1371/journal.ppat.0030139
学科分类:生物科学(综合)
来源: Public Library of Science
PDF
【 摘 要 】

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.

【 授权许可】

CC BY   

【 预 览 】
附件列表
Files Size Format View
RO201902010288587ZK.pdf 596KB PDF download
  文献评价指标  
  下载次数:15次 浏览次数:16次