Phospholipase D2 promotes degradation of hypoxia-inducible factor-1alpha independent of lipase activity.
- Author:
Mi Hee PARK
1
;
Sun Sik BAE
;
Kang Yell CHOI
;
Do Sik MIN
Author Information
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
- MeSH: 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
- From:Experimental & Molecular Medicine 2015;47(11):e196-
- CountryRepublic of Korea
- Language:English
- 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.
