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

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)

Abstract

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
Pages (from-to)e1006835
JournalPLoS Pathogens
Volume14
Issue number1
DOIs
Publication statusPublished - Jan 2018

Keywords

  • 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

Fingerprint

Dive into the research topics of 'Alphavirus-induced hyperactivation of PI3K/AKT directs pro-viral metabolic changes'. Together they form a unique fingerprint.

Cite this