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


CONCLUSIONS
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.
Sir
Donna
D
Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033, USA.
Chen
Wen-Ling
WL
Choi
Jinah
J
Wakita
Takaji
T
Yen
T S Benedict
TS
Ou
Jing-Hsiung James
JH
D001343:Autophagy / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000502:physiology; D016174:Hepacivirus / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology*; D006526:Hepatitis C / Q000503:physiopathology; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology / Q000821:virology; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000502:physiology; D010957:Plasmids; D017510:Protein Folding; D034741:RNA, Small Interfering / Q000494:pharmacology; D012367:RNA, Viral / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D044764:Ubiquitin-Activating Enzymes / Q000187:drug effects / Q000502:physiology; D014779:Virus Replication / Q000502:physiology
C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D012367:RNA, Viral; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes