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

Sir D., et al. Hepatology DOI: 10.1002/hep.22464 (2008)

Speaker: Po-Shun Wang (王柏舜)                         Time: 14:00-15:00, Sep. 24, 2008

Commentator: Dr. Huan-Yao Lei (黎煥耀老師)            Place: Room 601

Abstract:

Autophagy involves delivery of cytoplasmic cargo to the lysosomes. It removes long-lived proteins and damaged organelles in the cell for maintaining cellular homeostasis, and can serve as the innate immunity to protect organisms against intracellular pathogens ⁽¹⁾. As such, viruses have evolved diverse mechanisms to subvert the autophagic machinery for their replication and survival. Recently, hepatitis C virus (HCV) research has been facilitated by the development of a cell culture system for infectious HCV multiplication ⁽²⁾. The authors used this system and demonstrated that HCV could induce the accumulation of autophagosomes in cells, but could not enhance autophagic protein degradation. Instead, it is caused by suppressing the fusion of autophagosomes and lysosomes. Because endoplasmic reticulum (ER) stress, which is caused by the accumulation of misfolded proteins in the ER, can induce autophagy via the activation of unfolded protein response (UPR) ⁽³⁾, the authors further unraveled that the induction of autophagosomes by HCV is dependent on the UPR. The suppression of UPR signaling pathways inhibited the lipidation of microtubule-associated protein light chain 3 (LC3), an essential step for the autophagosome formation. Intriguingly, the authors further confirmed that the suppression of UPR or the expression of LC3 or Atg7 can decrease HCV RNA level, suggesting that ER stress and incomplete autophagic response play a positive role in HCV replication. Taken together, the authors' findings reveal the prolonged perturbation of the autophagic flux by HCV plays an important role in HCV pathogenesis.

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