title: Phospholipase D2 promotes degradation of hypoxia-inducible factor-1α independent of lipase activity.
abstract: Hypoxia-inducible factor-1α (HIF-1α) 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-1α 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-1α for ubiquitination and degradation. Here, we demonstrate that PLD2 protein itself interacts with HIF-1α, prolyl hydroxylase (PHD) and VHL to promote degradation of HIF-1α via the proteasomal pathway independent of lipase activity. PLD2 increases PHD2-mediated hydroxylation of HIF-1α by increasing the interaction of HIF-1α with PHD2. Moreover, PLD2 promotes VHL-dependent HIF-1α degradation by accelerating the association between VHL and HIF-1α. The interaction of the pleckstrin homology domain of PLD2 with HIF-1α also promoted degradation of HIF-1α and decreased expression of its target genes. These results indicate that PLD2 negatively regulates the stability of HIF-1α through the dynamic assembly of HIF-1α, PHD2 and VHL.
authors.affiliation: Department of Molecular Biology, College of Natural Science, Pusan National University, Busan, Republic of Korea.
authors.forename: Mi Hee
authors.initials: MH
authors.lastname: Park
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Busan, Republic of Korea.
authors.forename: Sun Sik
authors.initials: SS
authors.lastname: Bae
authors.affiliation: Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.|Translational Research Center for Protein Function Control, Yonsei University, Seoul, Republic of Korea.
authors.forename: Kang-Yell
authors.initials: KY
authors.lastname: Choi
authors.affiliation: Department of Molecular Biology, College of Natural Science, Pusan National University, Busan, Republic of Korea.|Translational Research Center for Protein Function Control, Yonsei University, Seoul, Republic of Korea.|Genetic Engineering Institute, Pusan National University, Busan, Republic of Korea.
authors.forename: Do Sik
authors.initials: do S
authors.lastname: Min
mesh_terms: D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D010739:Phospholipase D / Q000378:metabolism*; D064828:Prolyl Hydroxylases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D060066:Protein Interaction Maps; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064828:Prolyl Hydroxylases; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C105606:phospholipase D2; D010739:Phospholipase D; D046988:Proteasome Endopeptidase Complex; C497446:VHL protein, human