Hepatitis C virus (HCV) is an important human pathogen that can cause severe liver diseases including liver cirrhosis and hepatocellular carcinoma. Recently, our laboratory discovered that HCV could perturb the autophagic pathway, leading to the accumulation of autophagosomes in cells. Autophagy plays an important role in maintaining cellular homeostasis. The ability of HCV to persistently perturb the autophagic pathway during chronic infection can have profound consequences in HCV pathogenesis and oncogenesis. Our further studies revealed the association of the HCV RNA replication complex with autophagosomal membranes, suggesting that HCV induces autophagosomes to facilitate its RNA synthesis. HCV apparently induces autophagosomes by inhibiting their fusion with lysosomes. Interestingly, our preliminary studies also indicate that HCV induces the biogenesis of autophagosomes via a novel mechanism independent of the class 3 phosphatidylinositol-3-kinase (PI3KC3). In this application, we propose to continue our novel findings to study how HCV inhibits the maturation of autophagosomes. Specifically, we will test the hypothesis that HCV induces Rubicon to sequester UVRAG from the HOPS complex to inhibit the maturation of autophagosomes. In addition, we will also elucidate the molecular pathway of HCV-induced biogenesis of autophagosomes. Finally, we will also use a novel approach that we recently developed to purify autophagosomes from HCV-infected cells and to characterize their associated protein factors to understand the biogenesis of these membrane vesicles and the relationship between autophagosomes and the HCV RNA replication complex. Our proposed research will generate important information for us to understand the interaction between HCV and its host cell and lead to a better understanding of HCV replication and pathogenesis.

Public Health Relevance

Hepatitis C virus (HCV) is an important human pathogen. There are approximately 3.2 million people in the U.S. that are chronically infected by this virus. Many of these patients will develop severe liver diseases including liver cirrhosis and liver cancer and will require liver transplantation for survival. The goal of our proposed research is to understand the interaction between HCV and hepatocytes and how that interaction affects HCV replication and the progression of liver diseases. Our research will improve our knowledge about this important pathogen and lead to the improvements of treatments for HCV patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK094652-04
Application #
8724487
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Doo, Edward
Project Start
2011-09-21
Project End
2016-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Southern California
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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Luo, Guangxiang George; Ou, Jing-hsiung James (2015) Oncogenic viruses and cancer. Virol Sin 30:83-4
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Wang, Linya; Ou, Jing-hsiung James (2015) Hepatitis C virus and autophagy. Biol Chem 396:1215-22
Ou, Jing-Hsiung James (2014) Virus control goes epigenetic. PLoS Pathog 10:e1004370
Czaja, Mark J; Ding, Wen-Xing; Donohue Jr, Terrence M et al. (2013) Functions of autophagy in normal and diseased liver. Autophagy 9:1131-58
Liu, Zhe; Tian, Yongjun; Machida, Keigo et al. (2012) Transient activation of the PI3K-AKT pathway by hepatitis C virus to enhance viral entry. J Biol Chem 287:41922-30
Liu, Helene Minyi; Aizaki, Hideki; Machida, Keigo et al. (2012) Hepatitis C virus translation preferentially depends on active RNA replication. PLoS One 7:e43600
Klionsky, Daniel J (author list too long to display - see original citation for additional authors) (2012) Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8:445-544
Sir, Donna; Kuo, Cheng-fu; Tian, Yongjun et al. (2012) Replication of hepatitis C virus RNA on autophagosomal membranes. J Biol Chem 287:18036-43

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