Argininosuccinate synthetase 1 depletion produces a metabolic state conducive to herpes simplex virus 1 infection

Sarah L. Grady, John G. Purdy, Joshua D. Rabinowitz, Thomas Eugene Shenk

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Herpes simplex virus 1 (HSV-1) infection triggers specific metabolic changes in its host cell. To explore the interactions between cellular metabolism and HSV-1 infection, we performed an siRNA screen of cellular metabolic genes, measuring their effect on viral replication. The screen identified multiple enzymes predicted to influence HSV-1 replication, including argininosuccinate synthetase 1 (AS1), which consumes aspartate as part of de novo arginine synthesis. Knockdown of AS1 robustly enhanced viral genome replication and the production of infectious virus. Using high-resolution liquid chromatography-mass spectrometry, we found that the metabolic phenotype induced by knockdown of AS1 in human fibroblasts mimicked multiple aspects of the metabolic program observed during HSV-1 infection, including an increase in multiple nucleotides and their precursors. Together with the observation that AS1 protein and mRNA levels decrease during wild-type infection, this work suggests that reduced AS1 activity is partially responsible for the metabolic program induced by infection.

Original languageEnglish (US)
Pages (from-to)E5006-E5015
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number51
DOIs
StatePublished - Dec 17 2013

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Herpesviruses
  • Metabolomics

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