title: Unfolded protein response pathways regulate Hepatitis C virus replication via modulation of autophagy.
abstract: BACKGROUND
  Hepatitis C virus (HCV) induces endoplasmic reticulum (ER) stress which, in turn, activates the unfolding protein response (UPR). UPR activates three distinct signalling pathways. Additionally, UPR induces autophagy (UPR-autophagy pathways). On the other hand, it has become clear that some positive-single-strand RNA viruses utilize autophagy. Some groups have used the siRNA silencing approach to show that autophagy is required for HCV RNA replication. However, the mechanism of induction of the UPR-autophagy pathways remain unclear in the cells with HCV.
  
  
  RESULTS
  we used a genome-length HCV RNA (strain O of genotype 1b) replication system (OR6) in hepatoma cells (HuH-7-derived OR6 cells). As control, we used OR6c cells from which the HCV genome had been removed by treatment with interferon-α. The UPR-autophagy pathways were activated to a greater degree in the OR6 cells as compared to the OR6c cells. Rapamycin, mTOR-independent autophagy inducer, activated HCV replication in the OR6 cells. On the other hand, HCV replication in the cells was inhibited by 3-methyladenine (3-MA), which is an inhibitor of autophagy. Salubrinal (Eukaryotic Initiation Factor 2(eIF2)-alpha phosphatase inhibitor), 3-ethoxy-5, 6-dibromosalicylaldehyde (X-box binding protein-1 (XBP-1) splicing inhibitor) and sp600125 (c-Jun N-terminal kinases (JNK) inhibitor) inhibited HCV replication and autophagy. Additionally, HCV replication and autophagy were inhibited more strongly by combination of these inhibitors.
  
  
  CONCLUSIONS
  Our results suggest that UPR-autophagy pathways exert an influence on HCV replication. Therefore, control these pathways may serve as a novel therapeutic strategy against replication of HCV.
authors: Gastroenterology Division, Yokohama City University School of Medicine, 3-9, Fukuura, Kanazawa-ku, Yokohama City 236-0004, Japan.
authors: Yoshiyasu
authors: Y
authors: Shinohara
authors: Kento
authors: K
authors: Imajo
authors: Masato
authors: M
authors: Yoneda
authors: Wataru
authors: W
authors: Tomeno
authors: Yuji
authors: Y
authors: Ogawa
authors: Hiroyuki
authors: H
authors: Kirikoshi
authors: Kengo
authors: K
authors: Funakoshi
authors: Masanori
authors: M
authors: Ikeda
authors: Nobuyuki
authors: N
authors: Kato
authors: Atsushi
authors: A
authors: Nakajima
authors: Satoru
authors: S
authors: Saito
mesh_terms: D001343:Autophagy; D045744:Cell Line, Tumor; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D015398:Signal Transduction; D056811:Unfolded Protein Response / Q000187:drug effects / Q000502:physiology*; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*
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