An invertebrate Warburg effect: a shrimp virus achieves successful replication by altering the host metabolome via the PI3K-Akt-mTOR pathway

Mei-An Su; Yun-Tzu Huang; I-Tung Chen; Der-Yen Lee; Yun-Chieh Hsieh; Chun-Yuan Li; Tze Hann Ng; Suh-Yuen Liang; Shu-Yu Lin; Shiao-Wei Huang; Yi-An Chiang; Hon-Tsen Yu; Kay-Hooi Khoo; Geen-Dong Chang; Chu-Fang Lo; Han-Ching Wang

doi:10.1371/journal.ppat.1004196

An invertebrate Warburg effect: a shrimp virus achieves successful replication by altering the host metabolome via the PI3K-Akt-mTOR pathway

PLoS Pathog. 2014 Jun 12;10(6):e1004196. doi: 10.1371/journal.ppat.1004196. eCollection 2014 Jun.

Authors

Affiliations

¹ Institute of Biotechnology, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
² Institute of Zoology, College of Life Science, National Taiwan University, Taipei, Taiwan.
³ Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan; Center for Systems Biology, National Taiwan University, Taipei, Taiwan.
⁴ Core Facilities for Protein Structural Analysis, Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
⁵ Academia Sinica Common Mass Spectrometry Facilities at Institute of Biological Chemistry, Taipei, Taiwan.
⁶ Department of Life Science, College of Life Science, National Taiwan University, Taipei, Taiwan.
⁷ 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.
⁸ Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan.
⁹ Institute of Zoology, College of Life Science, National Taiwan University, Taipei, Taiwan; Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University, Tainan, Taiwan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acids / biosynthesis
Amino Acids / metabolism
Animals
Citric Acid Cycle / genetics
Energy Metabolism / genetics
Glycolysis / genetics
Mechanistic Target of Rapamycin Complex 1
Mechanistic Target of Rapamycin Complex 2
Metabolome / genetics
Monomeric GTP-Binding Proteins / genetics
Multiprotein Complexes / antagonists & inhibitors
Multiprotein Complexes / genetics
Naphthyridines / pharmacology
Penaeidae / metabolism*
Penaeidae / virology
Pentose Phosphate Pathway / genetics
Phosphatidylinositol 3-Kinases / metabolism*
Proteome / genetics
Proto-Oncogene Proteins c-akt / antagonists & inhibitors
Proto-Oncogene Proteins c-akt / metabolism*
TOR Serine-Threonine Kinases / antagonists & inhibitors
TOR Serine-Threonine Kinases / genetics
TOR Serine-Threonine Kinases / metabolism*
Virus Replication / genetics
White spot syndrome virus 1 / genetics*
White spot syndrome virus 1 / metabolism

Substances

1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one
Amino Acids
Multiprotein Complexes
Naphthyridines
Proteome
Mechanistic Target of Rapamycin Complex 1
Mechanistic Target of Rapamycin Complex 2
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases
Monomeric GTP-Binding Proteins

Grants and funding

This investigation was supported financially by the National Science Council (NSC 101-2321-B-006 -018 and NSC 102-2321-B-006 -008). The proteomic MS data were acquired at the former NRPGM Core Facilities for Proteomics and Glycomics (NSC 99-3112-B-001-025), at the Core Facilities for Protein Structural Analysis at Academia Sinica (NSC100-2325-B-001-029, NSC101-2319-B-001-003). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.