Phospholipase D1 protein coordinates dynamic assembly of HIF-1?-PHD-VHL to regulate HIF-1? stability.

ABSTRACT: Hypoxia-inducible factor-1? (HIF-1?) is a master transcriptional regulator of cellular response to hypoxia. In normoxia, HIF-1? is degraded through the prolyl hydroxylase (PHD) and von Hippel-Lindau (VHL) ubiquitination pathway. However, it is unknown whether PHD and VHL exert their enzymatic activities on HIF-1? separately or as a multiprotein complex. Here, we show that phospholipase D1 (PLD1) protein itself acts as a molecular platform, interacting directly with HIF-1?, PHD, and VHL, thereby dynamically assembling a multiprotein complex that mediates efficient degradation of HIF-1? in an O2-dependent manner. PLD1 depletion prevents degradation of HIF-1?; however, overall, PLD1 activity is predominantly involved in the upregulation of HIF-1? through increased translation, despite negative regulation of HIF-1? stability by PLD1 protein itself, suggesting dual roles of PLD1 in the regulation of HIF-1?. Disruption of the interactions of PLD1 with the proteins might be involved in hypoxic stabilization of HIF-1?. Interestingly, the pleckstrin homology domain interacting with these proteins promoted degradation of HIF-1? independent of oxygen concentration and suppressed tumor progression. These observations define a novel function of PLD1 as a previously unrecognized HIF-1? regulator.

SUBMITTER: Park MH 

PROVIDER: S-EPMC4323006 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature