Dysfunction of autophagy participates in vacuole formation and cell death in cells replicating Hepatitis C virus

Shuhei Taguwa, Hiroto Kambara, Naonobu Fujita, Takeshi Noda, Tamotsu Yoshimori, Kazuhiko Koike, Kohji Moriishi, Yoshiharu Matsuura

    Research output: Contribution to journalArticlepeer-review

    56 Citations (Scopus)

    Abstract

    Hepatitis C virus (HCV) is a major cause of chronic liver diseases. A high risk of chronicity is the major concern of HCV infection, since chronic HCV infection often leads to liver cirrhosis and hepatocellular carcinoma. Infection with the HCV genotype 1 in particular is considered a clinical risk factor for the development of hepatocellular carcinoma, although the molecular mechanisms of the pathogenesis are largely unknown. Autophagy is involved in the degradation of cellular organelles and the elimination of invasive microorganisms. In addition, disruption of autophagy often leads to several protein deposition diseases. Although recent reports suggest that HCV exploits the autophagy pathway for viral propagation, the biological significance of the autophagy to the life cycle of HCV is still uncertain. Here, we show that replication of HCV RNA induces autophagy to inhibit cell death. Cells harboring an HCV replicon RNA of genotype 1b strain Con1 but not of genotype 2a strain JFH1 exhibited an incomplete acidification of the autolysosome due to a lysosomal defect, leading to the enhanced secretion of immature cathepsin B. The suppression of autophagy in the Con1 HCV replicon cells induced severe cytoplasmic vacuolation and cell death. These results suggest that HCV harnesses autophagy to circumvent the harmful vacuole formation and to maintain a persistent infection. These findings reveal a unique survival strategy of HCV and provide new insights into the genotype-specific pathogenicity of HCV.

    Original languageEnglish
    Pages (from-to)13185-13194
    Number of pages10
    JournalJournal of virology
    Volume85
    Issue number24
    DOIs
    Publication statusPublished - 2011 Dec

    ASJC Scopus subject areas

    • Microbiology
    • Immunology
    • Insect Science
    • Virology

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