title: Argininosuccinate synthetase 1 depletion produces a metabolic state conducive to herpes simplex virus 1 infection.
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.
authors.affiliation: Departments of Molecular Biology and Chemistry, and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Grady
authors.forename: John G
authors.initials: JG
authors.lastname: Purdy
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Rabinowitz
authors.forename: Thomas
authors.initials: T
authors.lastname: Shenk
mesh_terms: D000818:Animals; D001124:Argininosuccinate Synthase / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D005347:Fibroblasts / Q000201:enzymology* / Q000473:pathology / Q000821:virology; D055785:Gene Knockdown Techniques; D016679:Genome, Viral / Q000502:physiology; D006561:Herpes Simplex / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014709:Vero Cells; D014779:Virus Replication / Q000502:physiology*
chemical_list: D012333:RNA, Messenger; D001124:Argininosuccinate Synthase
keywords: herpesviruses; metabolomics