Alphavirus-induced hyperactivation of PI3K/AKT directs pro-viral metabolic changes

Michela Mazzon*, Cecilia Castro*, Bastian Thaa, Lifeng Liu, Margit Mutso, Xiang Liu, Suresh Mahalingam, Julian L Griffin, Mark Marsh, Gerald M McInerney

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

45 Citations (Scopus)
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Virus reprogramming of cellular metabolism is recognised as a critical determinant for viral growth. While most viruses appear to activate central energy metabolism, different viruses have been shown to rely on alternative mechanisms of metabolic activation. Whether related viruses exploit conserved mechanisms and induce similar metabolic changes is currently unclear. In this work we investigate how two alphaviruses, Semliki Forest virus and Ross River virus, reprogram host metabolism and define the molecular mechanisms responsible. We demonstrate that in both cases the presence of a YXXM motif in the viral protein nsP3 is necessary for binding to the PI3K regulatory subunit p85 and for activating AKT. This leads to an increase in glucose metabolism towards the synthesis of fatty acids, although additional mechanisms of metabolic activation appear to be involved in Ross River virus infection. Importantly, a Ross River virus mutant that fails to activate AKT has an attenuated phenotype in vivo, suggesting that viral activation of PI3K/AKT contributes to virulence and disease.

Original languageEnglish
Article numbere1006835
Number of pages22
JournalPLoS Pathogens
Issue number1
Publication statusPublished - 29 Jan 2018

Bibliographical note

We thank our MRC-LMCB colleagues Dr Chiara Mencarelli who provided the rat cortical neurons used in this study, Dr Christin Luft for help with acquisition of high-content confocal images, and Dr Janos Kriston-Vizi for help with Fiji software. Dr Scott Lawrence kindly provided the SH-SY5Y cells. We thank Prof Andres Merits (University of Tartu, Estonia) for provision of nsP3 antibody and Dr Ji Luo (National Cancer Institute, USA) for provision of p85 expression plasmids.

Data Availability Statement

All relevant data are within the paper and its Supporting Information files.


  • Alphavirus/pathogenicity
  • Alphavirus Infections/metabolism
  • Animals
  • Cells, Cultured
  • Cricetinae
  • Enzyme Activation
  • Glucose/metabolism
  • Glycolysis/physiology
  • HEK293 Cells
  • Host-Pathogen Interactions
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Phosphatidylinositol 3-Kinases/metabolism
  • Proto-Oncogene Proteins c-akt/metabolism
  • Ross River virus/physiology
  • Semliki forest virus/physiology
  • Virulence


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