Exp Mol Med.  2015 Nov;47(11):e196. 10.1038/emm.2015.87.

Phospholipase D2 promotes degradation of hypoxia-inducible factor-1alpha independent of lipase activity

• Park MH
• Bae SS
• Choi KY
• Min DS

• KMID: 2359883
• DOI: http://doi.org/10.1038/emm.2015.87

Abstract

Hypoxia-inducible factor-1alpha (HIF-1alpha) is a key transcriptional mediator that coordinates the expression of various genes involved in tumorigenesis in response to changes in oxygen tension. The stability of HIF-1alpha protein is determined by oxygen-dependent prolyl hydroxylation, which is required for binding of the von Hippel-Lindau protein (VHL), the recognition component of an E3 ubiquitin ligase that targets HIF-1alpha for ubiquitination and degradation. Here, we demonstrate that PLD2 protein itself interacts with HIF-1alpha, prolyl hydroxylase (PHD) and VHL to promote degradation of HIF-1alpha via the proteasomal pathway independent of lipase activity. PLD2 increases PHD2-mediated hydroxylation of HIF-1alpha by increasing the interaction of HIF-1alpha with PHD2. Moreover, PLD2 promotes VHL-dependent HIF-1alpha degradation by accelerating the association between VHL and HIF-1alpha. The interaction of the pleckstrin homology domain of PLD2 with HIF-1alpha also promoted degradation of HIF-1alpha and decreased expression of its target genes. These results indicate that PLD2 negatively regulates the stability of HIF-1alpha through the dynamic assembly of HIF-1alpha, PHD2 and VHL.

MeSH Terms

Cell Line
HEK293 Cells
Humans
Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism
Phospholipase D/*metabolism
Prolyl Hydroxylases/metabolism
Proteasome Endopeptidase Complex/*metabolism
*Protein Interaction Maps
Proteolysis
Ubiquitin-Protein Ligases/metabolism
Von Hippel-Lindau Tumor Suppressor Protein/metabolism
Hypoxia-Inducible Factor 1, alpha Subunit
Phospholipase D
Prolyl Hydroxylases
Proteasome Endopeptidase Complex
Ubiquitin-Protein Ligases
Von Hippel-Lindau Tumor Suppressor Protein