J Biol Chem. 2010 Jun 25. [Epub ahead of print]
Toxoplasma gondii activates hypoxia inducible factor by stabilizing the HIF-1 alpha subunit via type I activin like receptor kinase receptor signaling
Wiley M, Sweeney KR, Chan DA, Brown KM, McMurtrey C, Howard EW, Giaccia AJ, Blader IJ.
University of Oklahoma Health Sciences Center, United States;
Toxoplasma gondii is an intracellular protozoan parasite that can cause devastating disease in fetuses and immune-compromised individuals. We previously reported that the alpha subunit of the host cell transcription factor, hypoxia-inducible factor-1 (HIF-1), is upregulated by infection and necessary for Toxoplasma growth. Under basal conditions, HIF-1alpha is constitutively expressed but rapidly targeted for proteasomal degradation after two proline residues are hydroxylated by a family of prolyl hydroxylases (PHDs). The PHDs are alpha-ketoglutarate-dependent dioxygenases that have low Kms for oxygen, making them important cellular oxygen sensors. Thus, when oxygen levels decrease HIF-1alpha is not hydroxylated, its levels increase, and HIF-1 is activated. How Toxoplasma activates HIF-1 under normoxic conditions remains unknown. Here, we report that Toxoplasma infection increases HIF-1alpha stability by preventing HIF-1alpha prolyl hydroxylation. Infection significantly decreases PHD2 abundance, which is the key prolyl hydroxylase for regulating HIF-1alpha. The effects of Toxoplasma on HIF-1alpha abundance and prolyl hydroxylase activity require Activin Like Receptor Kinase signaling.. Finally, parasite growth is severely diminished when signaling from this family of receptors is inhibited. Together, these data indicate that PHD2 is a key host cell factor for Toxoplasma gondii growth and represent a novel mechanism by which a microbial pathogen subverts host cell signaling and transcription to establish its replicative niche.
PMID: 20581113 [PubMed - as supplied by publisher]