title: An invertebrate Warburg effect: a shrimp virus achieves successful replication by altering the host metabolome via the PI3K-Akt-mTOR pathway.
abstract: In this study, we used a systems biology approach to investigate changes in the proteome and metabolome of shrimp hemocytes infected by the invertebrate virus WSSV (white spot syndrome virus) at the viral genome replication stage (12 hpi) and the late stage (24 hpi). At 12 hpi, but not at 24 hpi, there was significant up-regulation of the markers of several metabolic pathways associated with the vertebrate Warburg effect (or aerobic glycolysis), including glycolysis, the pentose phosphate pathway, nucleotide biosynthesis, glutaminolysis and amino acid biosynthesis. We show that the PI3K-Akt-mTOR pathway was of central importance in triggering this WSSV-induced Warburg effect. Although dsRNA silencing of the mTORC1 activator Rheb had only a relatively minor impact on WSSV replication, in vivo chemical inhibition of Akt, mTORC1 and mTORC2 suppressed the WSSV-induced Warburg effect and reduced both WSSV gene expression and viral genome replication. When the Warburg effect was suppressed by pretreatment with the mTOR inhibitor Torin 1, even the subsequent up-regulation of the TCA cycle was insufficient to satisfy the virus's requirements for energy and macromolecular precursors. The WSSV-induced Warburg effect therefore appears to be essential for successful viral replication.
authors.affiliation: Institute of Biotechnology, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Mei-An
authors.initials: MA
authors.lastname: Su
authors.affiliation: Institute of Biotechnology, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yun-Tzu
authors.initials: YT
authors.lastname: Huang
authors.affiliation: Institute of Zoology, College of Life Science, National Taiwan University, Taipei, Taiwan.
authors.forename: I-Tung
authors.initials: IT
authors.lastname: Chen
authors.affiliation: Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan; Center for Systems Biology, National Taiwan University, Taipei, Taiwan.
authors.forename: Der-Yen
authors.initials: DY
authors.lastname: Lee
authors.affiliation: Institute of Biotechnology, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yun-Chieh
authors.initials: YC
authors.lastname: Hsieh
authors.affiliation: Institute of Biotechnology, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chun-Yuan
authors.initials: CY
authors.lastname: Li
authors.affiliation: Institute of Biotechnology, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Tze Hann
authors.initials: TH
authors.lastname: Ng
authors.affiliation: Core Facilities for Protein Structural Analysis, Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Suh-Yuen
authors.initials: SY
authors.lastname: Liang
authors.affiliation: Academia Sinica Common Mass Spectrometry Facilities at Institute of Biological Chemistry, Taipei, Taiwan.
authors.forename: Shu-Yu
authors.initials: SY
authors.lastname: Lin
authors.affiliation: Department of Life Science, College of Life Science, National Taiwan University, Taipei, Taiwan.
authors.forename: Shiao-Wei
authors.initials: SW
authors.lastname: Huang
authors.affiliation: Institute of Biotechnology, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yi-An
authors.initials: YA
authors.lastname: Chiang
authors.affiliation: Department of Life Science, College of Life Science, National Taiwan University, Taipei, Taiwan.
authors.forename: Hon-Tsen
authors.initials: HT
authors.lastname: Yu
authors.affiliation: Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan; Core Facilities for Protein Structural Analysis, Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Kay-Hooi
authors.initials: KH
authors.lastname: Khoo
authors.affiliation: Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan.
authors.forename: Geen-Dong
authors.initials: GD
authors.lastname: Chang
authors.affiliation: Institute of Zoology, College of Life Science, National Taiwan University, Taipei, Taiwan; Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chu-Fang
authors.initials: CF
authors.lastname: Lo
authors.affiliation: Institute of Biotechnology, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Han-Ching
authors.initials: HC
authors.lastname: Wang
mesh_terms: D000596:Amino Acids / Q000096:biosynthesis / Q000378:metabolism; D000818:Animals; D002952:Citric Acid Cycle / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics; D006019:Glycolysis / Q000235:genetics; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D055442:Metabolome / Q000235:genetics; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000235:genetics; D009287:Naphthyridines / Q000494:pharmacology; D033561:Penaeidae / Q000378:metabolism* / Q000821:virology; D010427:Pentose Phosphate Pathway / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D020543:Proteome / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000235:genetics; D046848:White spot syndrome virus 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D000596:Amino Acids; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D020559:Monomeric GTP-Binding Proteins; D046912:Multiprotein Complexes; D009287:Naphthyridines; D019869:Phosphatidylinositol 3-Kinases; D020543:Proteome; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C553294:1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one