Editors' ChoiceHost-Pathogen Interactions

Viral Hypoxia Response

Science Signaling  30 Jul 2013:
Vol. 6, Issue 286, pp. ec174
DOI: 10.1126/scisignal.2004562

Several viruses stabilize hypoxia-inducible factor 1α (HIF-1α) to induce the hypoxic response in infected cells even under normoxic conditions. Vaccinia virus is used in the live vaccine against smallpox and is a useful delivery system for research purposes. Mazzon et al. performed a TAP (tandem affinity purification) screen with the vaccinia virus protein C16 and found that it bound to prolyl hydroxylase 2 (PHD2), the enzyme responsible for the initial modification that ultimately targets HIF-1α for degradation under normoxic conditions. In vitro binding assays with purified recombinant C16 and the C-terminal residues of PHD2 (containing the catalytic domain) showed that the interaction was direct. Molecular modeling analysis indicated that the N-terminal portion of C16 adopted a secondary structure similar to that of the catalytic domain of PHD2, and C16 lacking this region did not bind to PHD2. C16 inhibited the in vitro hydroxylation of a domain of HIF-1α that is a substrate for PHD2 by the catalytic portion of PHD2. The abundances of HIF-1α and the mRNAs for two HIF-1α target genes were increased in cells transfected with C16 but not another viral protein. Nuclear translocation of HIF-1α and induction of HIF-1α target gene expression occurred in cells infected with wild-type virus but not virus lacking C16. Viruses may activate this hypoxic response to reprogram the infected cells into a state more conducive to viral replication, and vaccinia virus now joins the ranks of several other viruses, including oncogenic viruses, that trigger this response.

M. Mazzon, N. E. Peters, C. Loenarz, E. M. Krysztofinska, S. W. J. Ember, B. J. Ferguson, G. L. Smith, A mechanism for induction of a hypoxic response by vaccinia virus. Proc. Natl. Acad. Sci. U.S.A. 110, 12444–12449 (2013). [Abstract] [Full Text]