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

doi:10.1371/journal.ppat.1006835

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

The Rowett Institute of Nutrition and Health

Research output: Contribution to journal › Article › peer-review

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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 language	English
Article number	e1006835
Number of pages	22
Journal	PLoS Pathogens
Volume	14
Issue number	1
DOIs	https://doi.org/10.1371/journal.ppat.1006835
Publication status	Published - 29 Jan 2018

Bibliographical note

Acknowledgments
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.

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

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Cite this

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title = "Alphavirus-induced hyperactivation of PI3K/AKT directs pro-viral metabolic changes",

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.",

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author = "Michela Mazzon and Cecilia Castro and Bastian Thaa and Lifeng Liu and Margit Mutso and Xiang Liu and Suresh Mahalingam and Griffin, {Julian L} and Mark Marsh and McInerney, {Gerald M}",

note = "Acknowledgments 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.",

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AU - Marsh, Mark

AU - McInerney, Gerald M

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N2 - 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.

AB - 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.

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KW - HEK293 Cells

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KW - Mice

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KW - Phosphatidylinositol 3-Kinases/metabolism

KW - Proto-Oncogene Proteins c-akt/metabolism

KW - Ross River virus/physiology

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KW - Virulence

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DO - 10.1371/journal.ppat.1006835

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IS - 1

M1 - e1006835

ER -

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

Abstract

Bibliographical note

Data Availability Statement

Keywords

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