Park Mi Hee, Choi Kang-Yell, Min Do Sik
Department of Molecular Biology, College of Natural Science, Pusan National University, Busan, Republic of Korea.
Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
Exp Mol Med. 2015 Dec 18;47(12):e200. doi: 10.1038/emm.2015.101.
Endocytosis is differentially regulated by hypoxia-inducible factor-1α (HIF-1α) and phospholipase D (PLD). However, the relationship between HIF-1α and PLD in endocytosis is unknown. HIF-1α is degraded through the prolyl hydroxylase (PHD)/von Hippel-Lindau (VHL) ubiquitination pathway in an oxygen-dependent manner. Here, we show that PLD1 recovers the decrease in epidermal growth factor receptor (EGFR) endocytosis induced by HIF-1α independent of lipase activity via the Rab5-mediated endosome fusion pathway. EGF-induced interaction of PLD1 with HIF-1α, PHD and VHL may contribute to EGFR endocytosis. The pleckstrin homology domain (PH) of PLD1 itself promotes degradation of HIF-1α, then accelerates EGFR endocytosis via upregulation of rabaptin-5 and suppresses tumor progression. These findings reveal a novel role of the PLD1-PH domain as a positive regulator of endocytosis and provide a link between PLD1 and HIF-1α in the EGFR endocytosis pathway.
内吞作用受缺氧诱导因子-1α（HIF-1α）和磷脂酶D（PLD）的差异性调控。然而，HIF-1α与PLD在内吞作用中的关系尚不清楚。HIF-1α通过脯氨酰羟化酶（PHD）/冯·希佩尔-林道（VHL）泛素化途径以氧依赖的方式降解。在此，我们表明PLD1通过Rab5介导的内体融合途径恢复由HIF-1α诱导的表皮生长因子受体（EGFR）内吞作用的减少，且不依赖于脂肪酶活性。表皮生长因子（EGF）诱导的PLD1与HIF-1α、PHD和VHL的相互作用可能有助于EGFR内吞作用。PLD1自身的普列克底物蛋白同源结构域（PH）促进HIF-1α的降解，进而通过上调rabaptin-5加速EGFR内吞作用并抑制肿瘤进展。这些发现揭示了PLD1-PH结构域作为内吞作用正调控因子的新作用，并在EGFR内吞作用途径中建立了PLD1与HIF-1α之间的联系。
