Unfolded protein response pathways regulate Hepatitis C virus replication via modulation of autophagy

Yoshiyasu Shinohara, Kento Imajo, Masato Yoneda, Wataru Tomeno, Yuji Ogawa, Hiroyuki Kirikoshi, Kengo Funakoshi, Masanori Ikeda, Nobuyuki Kato, Atsushi Nakajima, Satoru Saito

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)


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. Method and 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)326-332
Number of pages7
JournalBiochemical and Biophysical Research Communications
Issue number2
Publication statusPublished - Mar 8 2013
Externally publishedYes


  • Autophagy
  • EIF2-alpha
  • Hepatitis C virus
  • JNK
  • Unfolding protein response
  • XBP-1

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology


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