title: Pegylated IFN-α suppresses hepatitis C virus by promoting the DAPK-mTOR pathway.
abstract: Death-associated protein kinase (DAPK) has been found to be induced by IFN, but its antiviral activity remains elusive. Therefore, we investigated whether DAPK plays a role in the pegylated IFN-α (peg-IFN-α)-induced antiviral activity against hepatitis C virus (HCV) replication. Primary human hepatocytes, Huh-7, and infectious HCV cell culture were used to study the relationship between peg-IFN-α and the DAPK-mammalian target of rapamycin (mTOR) pathways. The activation of DAPK and signaling pathways were determined using immunoblotting. By silencing DAPK and mTOR, we further assessed the role of DAPK and mTOR in the peg-IFN-α-induced suppression of HCV replication. Peg-IFN-α up-regulated the expression of DAPK and mTOR, which was associated with the suppression of HCV replication. Overexpression of DAPK enhanced mTOR expression and then inhibited HCV replication. In addition, knockdown of DAPK reduced the expression of mTOR in peg-IFN-α-treated cells, whereas silencing of mTOR had no effect on DAPK expression, suggesting mTOR may be a downstream effector of DAPK. More importantly, knockdown of DAPK or mTOR significantly mitigated the inhibitory effects of peg-IFN-α on HCV replication. In conclusion, our data suggest that the DAPK-mTOR pathway is critical for anti-HCV effects of peg-IFN-α.
authors.affiliation: Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and Hospital, Taipei 10002, Taiwan.|National Mosquito-Borne Diseases Control Research Center, National Health Research Institutes, Miaoli 35053, Taiwan.
authors.forename: Wei-Liang
authors.initials: WL
authors.lastname: Liu
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan.|Department of Microbiology, National Taiwan University College of Medicine, Taipei 10051, Taiwan.
authors.forename: Hung-Chih
authors.initials: HC
authors.lastname: Yang
authors.affiliation: Liver Diseases Research Center, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taipei 23142, Taiwan.|Post-Baccalaureate Chinese Medicine, Tzu Chi University School, Hualien 97004, Taiwan.
authors.forename: Ching-Sheng
authors.initials: CS
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and Hospital, Taipei 10002, Taiwan.
authors.forename: Chih-Chiang
authors.initials: CC
authors.lastname: Wang
authors.affiliation: Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and Hospital, Taipei 10002, Taiwan.
authors.forename: Tzu-San
authors.initials: TS
authors.lastname: Wang
authors.affiliation: Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and Hospital, Taipei 10002, Taiwan; kaojh@ntu.edu.tw chends@ntu.edu.tw.|Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan.|Hepatitis Research Center, National Taiwan University Hospital, Taipei 10002, Taiwan.
authors.forename: Jia-Horng
authors.initials: JH
authors.lastname: Kao
authors.affiliation: Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and Hospital, Taipei 10002, Taiwan; kaojh@ntu.edu.tw chends@ntu.edu.tw.|Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan.|Hepatitis Research Center, National Taiwan University Hospital, Taipei 10002, Taiwan.|Genomics Research Center, Academia Sinica, Nankang, Taipei 11529, Taiwan.
authors.forename: Ding-Shinn
authors.initials: DS
authors.lastname: Chen
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival; D064550:Death-Associated Protein Kinases / Q000378:metabolism*; D020868:Gene Silencing; D005838:Genotype; D056945:Hep G2 Cells; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D006526:Hepatitis C / Q000378:metabolism*; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D011092:Polyethylene Glycols; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects; D054462:p21-Activated Kinases / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C546842:MTOR protein, human; C579096:DAPK1 protein, human; D064550:Death-Associated Protein Kinases; C515903:PAK1 protein, human; D058570:TOR Serine-Threonine Kinases; D054462:p21-Activated Kinases
keywords: DAPK; PAK-1; hepatitis C virus; mTOR; peg-IFN-α