title: Downregulation of autophagy-related gene ATG5 and GABARAP expression by IFN-λ1 contributes to its anti-HCV activity in human hepatoma cells.
abstract: Type-III interferon (IFN-λ), the most recently discovered family of IFNs, shares common features with type I IFNs, but also has many distinctive activities. It is not clear that whether IFN-λ has additional antiviral mechanisms. In this study, we investigated the effects of IFN-λ on autophagy, a cellular process closely related to hepatitis C virus (HCV) infection in human hepatoma Huh7 cells. Our results showed that IFN-λ1 treatment inhibit autophagic activity in Huh7 cells, as evidenced by the decreased expression of microtubule-associated protein 1 light chain 3B (LC3B)-II and conversion of LC3B-I to LC3B-II, decreased formation of GFP-LC3 puncta and accumulation of autophagosomes. IFN-λ1 could also inhibit HCV-induced or tunicamycin (a known inducer of autophagy with similar mechanism to HCV infection) -induced LC3B-II expression and autophagosome formation. Through PCR array, real time RT PCR, and western blot, two autophagy-related genes, ATG5 and GABARAP, were identified and verified to be down-regulated by IFN-λ1 treatment, either in HCV-uninfected Huh7 cells or in HCV JFH-1-infected cells. Overexpression of ATG5 and/or GABARAP could partly recover the IFN-λ1-inhibited HCV replication. Mechanism research demonstrated that IFN-λ1 could induce the expression of miR-181a and miR-214 (targeting ATG5 and GABARAP respectively), by which down-regulates ATG5 and GABARAP expression. Taken together, our results indicate that suppression of the autophagy response by IFN-λ1 contributes to IFN-λ1 anti-HCV activity. The results also provide a theoretical basis for improving the effectiveness of IFN treatment of HCV infection through inhibition of the HCV-induced autophagy response.
authors.affiliation: Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China; Guangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Li
authors.affiliation: Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China; Medical Insurance Department, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, Guangxi, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.affiliation: Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China; Guangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China.
authors.forename: Shoucai
authors.initials: S
authors.lastname: Fang
authors.affiliation: Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China; Division of HIV/AIDS Control and Prevention, Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention, Nanning, 530021, Guangxi, China.
authors.forename: Jinming
authors.initials: J
authors.lastname: Su
authors.affiliation: Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China; Guangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China.
authors.forename: Junjun
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China; Guangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China.
authors.forename: Bingyu
authors.initials: B
authors.lastname: Liang
authors.affiliation: Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China; Guangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China.
authors.forename: Jiegang
authors.initials: J
authors.lastname: Huang
authors.affiliation: Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China; Guangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China; Guangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Zang
authors.affiliation: Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA, 19140, USA.
authors.forename: Wenzhe
authors.initials: W
authors.lastname: Ho
authors.affiliation: Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA, 19140, USA.
authors.forename: Jieliang
authors.initials: J
authors.lastname: Li
authors.affiliation: Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Li
authors.affiliation: Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China; Geriatrics Digestion Department of Internal Medicine, The First Affiliated Hospital of GuangXi Medical University, Nanning, 530021, Guangxi, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China; Guangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China. Electronic address: yeli@gxmu.edu.cn.
authors.forename: Li
authors.initials: L
authors.lastname: Ye
authors.affiliation: Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China; Guangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China. Electronic address: lianghao@gxmu.edu.cn.
authors.forename: Hao
authors.initials: H
authors.lastname: Liang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000998:Antiviral Agents / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000187:drug effects; D000071187:Autophagy-Related Protein 5 / Q000235:genetics*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy; D022781:Hepatocytes / Q000187:drug effects / Q000821:virology; D006801:Humans; D007372:Interferons / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000821:virology; D035683:MicroRNAs / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D015398:Signal Transduction; D014779:Virus Replication / Q000187:drug effects
chemical_list: C502778:ATG5 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000998:Antiviral Agents; D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; C116741:GABARAP protein, human; C547397:MIRN214 microRNA, human; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D008869:Microtubule-Associated Proteins; D007372:Interferons
keywords: ATG5; Autophagy; GABARAP; Hepatitis C virus; IFN-λ