title: Regulation of autophagic activation by Rta of Epstein-Barr virus via the extracellular signal-regulated kinase pathway.
abstract: Autophagy is an intracellular degradation pathway that provides a host defense mechanism against intracellular pathogens. However, many viruses exploit this mechanism to promote their replication. This study shows that lytic induction of Epstein-Barr virus (EBV) increases the membrane-bound form of LC3 (LC3-II) and LC3-containing punctate structures in EBV-positive cells. Transfecting 293T cells with a plasmid that expresses Rta also induces autophagy, revealing that Rta is responsible for autophagic activation. The activation involves Atg5, a key component of autophagy, but not the mTOR pathway. The expression of Rta also activates the transcription of the genes that participate in the formation of autophagosomes, including LC3A, LC3B, and ATG9B genes, as well as those that are involved in the regulation of autophagy, including the genes TNF, IRGM, and TRAIL. Additionally, treatment with U0126 inhibits the Rta-induced autophagy and the expression of autophagy genes, indicating that the autophagic activation is caused by the activation of extracellular signal-regulated kinase (ERK) signaling by Rta. Finally, the inhibition of autophagic activity by an autophagy inhibitor, 3-methyladenine, or Atg5 small interfering RNA, reduces the expression of EBV lytic proteins and the production of viral particles, revealing that autophagy is critical to EBV lytic progression. This investigation reveals how an EBV-encoded transcription factor promotes autophagy to affect viral lytic development.
authors.affiliation: Graduate Institute of Clinical Medical Sciences, Chang-Gung University, Taoyuan, Taiwan hungc01@mail.cgu.edu.tw cgliu@mail.cgu.edu.tw.
authors.forename: Chien-Hui
authors.initials: CH
authors.lastname: Hung
authors.affiliation: Department of Respiratory Care, Chung-Gung University of Science and Technology, Chiayi, Taiwan.
authors.forename: Lee-Wen
authors.initials: LW
authors.lastname: Chen
authors.affiliation: Molecular Genetics Laboratory, Department of Microbiology and Immunology, College of Medicine, Chang-Gung University, Taoyuan, Taiwan.
authors.forename: Wen-Hung
authors.initials: WH
authors.lastname: Wang
authors.affiliation: Graduate Institute of Clinical Medical Sciences, Chang-Gung University, Taoyuan, Taiwan.
authors.forename: Pey-Jium
authors.initials: PJ
authors.lastname: Chang
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Ya-Fang
authors.initials: YF
authors.lastname: Chiu
authors.affiliation: Molecular Genetics Laboratory, Department of Microbiology and Immunology, College of Medicine, Chang-Gung University, Taoyuan, Taiwan.
authors.forename: Chen-Chia
authors.initials: CC
authors.lastname: Hung
authors.affiliation: Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Ying-Ju
authors.initials: YJ
authors.lastname: Lin
authors.affiliation: Department of Medical Research, Chang-Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Jieh-Yuan
authors.initials: JY
authors.lastname: Liou
authors.affiliation: Graduate Institute of Clinical Medical Sciences, Chang-Gung University, Taoyuan, Taiwan.
authors.forename: Wan-Ju
authors.initials: WJ
authors.lastname: Tsai
authors.affiliation: Graduate Institute of Clinical Medical Sciences, Chang-Gung University, Taoyuan, Taiwan.
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Hung
authors.affiliation: Molecular Genetics Laboratory, Department of Microbiology and Immunology, College of Medicine, Chang-Gung University, Taoyuan, Taiwan hungc01@mail.cgu.edu.tw cgliu@mail.cgu.edu.tw.
authors.forename: Shih-Tung
authors.initials: ST
authors.lastname: Liu
mesh_terms: D001343:Autophagy; D001483:Base Sequence; D017931:DNA Primers; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D057809:HEK293 Cells; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000502:physiology*; D046529:Microscopy, Electron, Transmission; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015534:Trans-Activators / Q000502:physiology*
chemical_list: C068382:BRLF1 protein, Human herpesvirus 4; D017931:DNA Primers; D017874:Immediate-Early Proteins; D015534:Trans-Activators; D048049:Extracellular Signal-Regulated MAP Kinases