A mechanism for induction of a hypoxic response by vaccinia virus

作者：Mazzon Michela; Peters Nicholas E; Loenarz Christoph; Krysztofinska Ewelina M; Ember Stuart W J; Ferguson Brian J; Smith Geoffrey L^*

来源：Proceedings of the National Academy of Sciences, 2013, 110(30): 12444-12449.

DOI：10.1073/pnas.1302140110

• Orthopoxvirus
• variola virus
• Warburg effect
• glucose metabolism

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)-1 alpha, 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-1 alpha 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-1 alpha. The binding between C16 and PHD2 is direct and specific, and ectopic expression of C16 alone induces transcription of HIF-1 alpha responsive genes. Conversely, a VACV strain lacking the gene for C16, C16L, is unable to induce HIF-1 alpha 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.

• 出版日期2013-7-23