Induction of incomplete autophagic response by hepatitis C virus via the unfolded protein response

Authors

  • Donna Sir,

    1. Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, California
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  • Wen-ling Chen,

    1. Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, California
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  • Jinah Choi,

    1. Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, California
    Current affiliation:
    1. School of Natural Sciences, University of California, Merced, CA
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  • Takaji Wakita,

    1. Department of Virology II, National Institute of Infectious Diseases, Shinjuku, Tokyo, Japan
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  • T.S. Benedict Yen,

    1. Pathology Service, Veterans Affairs Medical Center, and Department of Pathology, University of California, San Francisco, San Francisco, CA
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  • Jing-hsiung James Ou

    Corresponding author
    1. Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, California
    • Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033
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    • fax: 323-442-1721


  • Potential conflict of interest: Nothing to report.

Abstract

Autophagy is important for cellular homeostasis and can serve as innate immunity to remove intracellular pathogens. Here, we demonstrate by a battery of morphological and biochemical assays that hepatitis C virus (HCV) induces the accumulation of autophagosomes in cells without enhancing autophagic protein degradation. This induction of autophagosomes depended on the unfolded protein response (UPR), as the suppression of UPR signaling pathways suppressed HCV-induced lipidation of the microtubule-associated protein light chain 3 (LC3) protein, a necessary step for the formation of autophagosomes. The suppression of UPR or the suppression of expression of LC3 or Atg7, a protein that mediates LC3 lipidation, suppressed HCV replication, indicating a positive role of UPR and the incomplete autophagic response in HCV replication. Conclusion: Our studies delineate the molecular pathway by which HCV induces autophagic vacuoles and also demonstrate the perturbation of the autophagic response by HCV. These unexpected effects of HCV on the host cell likely play an important role in HCV pathogenesis. (HEPATOLOGY 2008.)

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