title: A role for vaccinia virus protein C16 in reprogramming cellular energy metabolism.
abstract: Vaccinia virus (VACV) is a large DNA virus that replicates in the cytoplasm and encodes about 200 proteins of which approximately 50 % may be non-essential for viral replication. These proteins enable VACV to suppress transcription and translation of cellular genes, to inhibit the innate immune response, to exploit microtubule- and actin-based transport for virus entry and spread, and to subvert cellular metabolism for the benefit of the virus. VACV strain WR protein C16 induces stabilization of the hypoxia-inducible transcription factor (HIF)-1α by binding to the cellular oxygen sensor prolylhydroxylase domain-containing protein (PHD)2. Stabilization of HIF-1α is induced by several virus groups, but the purpose and consequences are unclear. Here, (1)H-NMR spectroscopy and liquid chromatography-mass spectrometry are used to investigate the metabolic alterations during VACV infection in HeLa and 2FTGH cells. The role of C16 in such alterations was examined by comparing infection to WT VACV (strain WR) and a derivative virus lacking gene C16L (vΔC16). Compared with uninfected cells, VACV infection caused increased nucleotide and glutamine metabolism. In addition, there were increased concentrations of glutamine derivatives in cells infected with WT VACV compared with vΔC16. This indicates that C16 contributes to enhanced glutamine metabolism and this may help preserve tricarboxylic acid cycle activity. These data show that VACV infection reprogrammes cellular energy metabolism towards increased synthesis of the metabolic precursors utilized during viral replication, and that C16 contributes to this anabolic reprogramming of the cell, probably via the stabilization of HIF-1α.
authors.affiliation: Department of Pathology, Tennis Court Road, University of Cambridge, Cambridge CB2 1QP, UK.
authors.forename: Michela
authors.initials: M
authors.lastname: Mazzon
authors.affiliation: Department of Biochemistry and Cambridge Systems Biology Centre, Tennis Court Road, University of Cambridge, Cambridge CB2 1GA, UK.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Castro
authors.affiliation: Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory, Fulborn Road, Cambridge CB1 9NL, UK.|Department of Biochemistry and Cambridge Systems Biology Centre, Tennis Court Road, University of Cambridge, Cambridge CB2 1GA, UK.
authors.forename: Lee D
authors.initials: LD
authors.lastname: Roberts
authors.affiliation: Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory, Fulborn Road, Cambridge CB1 9NL, UK.|Department of Biochemistry and Cambridge Systems Biology Centre, Tennis Court Road, University of Cambridge, Cambridge CB2 1GA, UK.
authors.forename: Julian L
authors.initials: JL
authors.lastname: Griffin
authors.affiliation: Department of Pathology, Tennis Court Road, University of Cambridge, Cambridge CB2 1QP, UK.
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Smith
mesh_terms: D002460:Cell Line; D004734:Energy Metabolism; D017353:Gene Deletion; D054884:Host-Pathogen Interactions; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D055550:Protein Stability; D014616:Vaccinia virus / Q000235:genetics / Q000502:physiology*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014764:Viral Proteins