title: Autophagy is involved in regulating influenza A virus RNA and protein synthesis associated with both modulation of Hsp90 induction and mTOR/p70S6K signaling pathway.
abstract: Influenza A virus (IAV) infection triggers autophagosome formation, but inhibits the fusion of autophagosomes with lysosomes. However, the role of autophagy in IAV replication is still largely unclarified. In this study, we aim to reveal the role of autophagy in IAV replication and the molecular mechanisms underlying the regulation. By using autophagy-deficient (Atg7(-/-)) MEFs, we demonstrated that autophagy deficiency significantly reduced the levels of viral proteins, mRNA and genomic RNAs (vRNAs) without affecting viral entry. We further found that autophagy deficiency lead to a transient increase in phosphorylation of mTOR and its downstream targets including 4E-BP1 and S6 at a very early stage of IAV infection, and markedly suppressed p70S6K phosphorylation at the late stage of IAV infection. Furthermore, autophagy deficiency resulted in impairment of Hsp90 induction in response to IAV infection. These results indicate that IAV regulates autophagy to benefit the accumulation of viral elements (synthesis of viral proteins and genomic RNA) during IAV replication. This regulation is associated with modulation of Hsp90 induction and mTOR/p70S6K signaling pathway. Our results provide important evidence for the role of autophagy in IAV replication and the mechanisms underlying the regulation.
authors.affiliation: Division of Molecular Pharmacology of Infectious Agents, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521, Japan.
authors.forename: Ge
authors.initials: G
authors.lastname: Liu
authors.affiliation: Biomedical R&D Center, Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, Guangdong 510632, China.
authors.forename: Meigong
authors.initials: M
authors.lastname: Zhong
authors.affiliation: Division of Molecular Pharmacology of Infectious Agents, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521, Japan.
authors.forename: Chaowan
authors.initials: C
authors.lastname: Guo
authors.affiliation: Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yan-Sen University, 132 Ease Circle Road at University City, Guangzhou 510006, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.affiliation: Biomedical R&D Center, Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, Guangdong 510632, China. Electronic address: twang-yf@163.com.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Molecular Pharmacology of Infectious Agents, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521, Japan. Electronic address: kkholi@nagasaki-u.ac.jp.
authors.forename: Kaio
authors.initials: K
authors.lastname: Kitazato
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002460:Cell Line; D004285:Dogs; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D047348:Hydrolyzable Tannins / Q000494:pharmacology; D009980:Influenza A virus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014764:Viral Proteins / Q000096:biosynthesis* / Q000378:metabolism
chemical_list: D018841:HSP90 Heat-Shock Proteins; D047348:Hydrolyzable Tannins; D012333:RNA, Messenger; D012367:RNA, Viral; D014764:Viral Proteins; C435084:pentagalloylglucose; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases
keywords: Autophagy; Hsp90; Influenza A virus; Pentagalloyl glucose; Viral RNA and protein synthesis; mTOR signal pathway