title: The microRNA-99 family modulates hepatitis B virus replication by promoting IGF-1R/PI3K/Akt/mTOR/ULK1 signaling-induced autophagy.
abstract: MicroRNAs are small highly conserved noncoding RNAs that are widely expressed in multicellular organisms and participate in the regulation of various cellular processes including autophagy and viral replication. Evidently, microRNAs are able to modulate host gene expression and thereby inhibit or enhance hepatitis B virus (HBV) replication. The miR-99 family members are highly expressed in the liver. Interestingly, the plasma levels of miR-99 family in the peripheral blood correspond with HBV DNA loads. Thus, we asked whether the miR-99 family regulated HBV replication and analyzed the underlying molecular mechanism. Compared with primary hepatocytes, miR-99 family expression was downregulated in hepatoma cells. Transfection of miR-99a, miR-99b, and miR-100 markedly increased HBV replication, progeny secretion, and antigen expression in hepatoma cells. However, miR-99 family had no effect on HBV transcription and HBV promoter activities, suggesting that they regulate HBV replication at posttranscriptional steps. Consistent with bioinformatic analysis and recent reports, ectopic expression of miR-99 family attenuated IGF-1R/Akt/mTOR pathway signaling and repressed insulin-stimulated activation in hepatoma cells. Moreover, the experimental data demonstrated that the miR-99 family promoted autophagy through mTOR/ULK1 signaling and thereby enhanced HBV replication. In conclusion, the miR-99 family promotes HBV replication posttranscriptionally through IGF-1R/PI3K/Akt/mTOR/ULK1 signaling-induced autophagy.
authors.affiliation: Institute of Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Institute of Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Wanyu
authors.initials: W
authors.lastname: Deng
authors.affiliation: Institute of Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Jinke
authors.initials: J
authors.lastname: Pang
authors.affiliation: Institute of Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Thekla
authors.initials: T
authors.lastname: Kemper
authors.affiliation: Institute of Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.|Wuxi Medical School, Jiangnan University, Wuxi, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
authors.affiliation: The Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yin
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Jiming
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Mengji
authors.initials: M
authors.lastname: Lu
mesh_terms: D001343:Autophagy / Q000276:immunology*; D000071189:Autophagy-Related Protein-1 Homolog / Q000378:metabolism; D015870:Gene Expression; D015967:Gene Expression Regulation, Viral; D056945:Hep G2 Cells; D006509:Hepatitis B / Q000276:immunology / Q000821:virology*; D006515:Hepatitis B virus / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D035683:MicroRNAs / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014764:Viral Proteins / Q000096:biosynthesis / Q000235:genetics; D014779:Virus Replication
chemical_list: D000071189:Autophagy-Related Protein-1 Homolog; D047908:Intracellular Signaling Peptides and Proteins; D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin; D058570:TOR Serine-Threonine Kinases; D014764:Viral Proteins; C000597236:IGF1R protein, human; C544266:MIRN100 microRNA, human; C561679:MIRN99 microRNA, human; C546842:MTOR protein, human; C484754:ULK1 protein, human
keywords: IGF-1R/PI3K/Akt/mTOR/ULK1 signaling; autophagy; hepatitis B virus; miR-99 family