title: A mechanism for induction of a hypoxic response by vaccinia virus.
abstract: Viruses have evolved sophisticated strategies to exploit host cell function for their benefit. Here we show that under physiologically normal oxygen levels (normoxia) vaccinia virus (VACV) infection leads to a rapid stabilization of hypoxia-inducible factor (HIF)-1α, its translocation into the nucleus and the activation of HIF-responsive genes, such as vascular endothelial growth factor (VEGF), glucose transporter-1, and pyruvate dehydrogenase kinase-1. HIF-1α stabilization is mediated by VACV protein C16 that binds the human oxygen sensing enzyme prolyl-hydroxylase domain containing protein (PHD)2 and thereby inhibits PHD2-dependent hydroxylation of HIF-1α. The binding between C16 and PHD2 is direct and specific, and ectopic expression of C16 alone induces transcription of HIF-1α responsive genes. Conversely, a VACV strain lacking the gene for C16, C16L, is unable to induce HIF-1α stabilization. Interestingly, the N-terminal region of C16 is predicted to have a PHD2-like structural fold but lacks the catalytic active site residues of PHDs. The induction of a hypoxic response by VACV is reminiscent of the biochemical consequences of solid tumor formation, and illustrates a poxvirus strategy for manipulation of cellular gene expression and biochemistry.
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom.
authors.forename: Michela
authors.initials: M
authors.lastname: Mazzon
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Peters
authors.forename: Christoph
authors.initials: C
authors.lastname: Loenarz
authors.forename: Ewelina M
authors.initials: EM
authors.lastname: Krysztofinska
authors.forename: Stuart W J
authors.initials: SW
authors.lastname: Ember
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Ferguson
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Smith
mesh_terms: D000595:Amino Acid Sequence; D015687:Cell Hypoxia / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D006900:Hydroxylation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D008969:Molecular Sequence Data; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014616:Vaccinia virus / Q000502:physiology*; D014764:Viral Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014764:Viral Proteins; C490190:EGLN1 protein, human; D011393:Procollagen-Proline Dioxygenase; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases
keywords: Orthopoxvirus; Warburg effect; glucose metabolism; variola virus