Okano Makoto, Matsuo Hiromi, Nishimura Yuya, Hozumi Katsuto, Yoshioka Saho, Tonoki Ayako, Itoh Motoyuki
Graduate School of Science, Nagoya University, Nagoya, Aichi, 464-8602, Japan.
Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan.
Genes Cells. 2016 May;21(5):425-41. doi: 10.1111/gtc.12350. Epub 2016 Feb 28.
Notch signaling regulates normal development and tissue homeostasis. Ligand endocytosis plays critical roles in Notch signaling activation. Endocytic proteins such as epsin and dynamin participate in Notch ligand activity by mediating Notch ligand endocytosis. The ubiquitin ligase Mib1 also plays essential roles in Notch signaling via Notch ligand ubiquitination. However, the molecular links between Mib1 and endocytic proteins have not been fully defined. Here, we show that Mib1 is involved in dynamin 2 recruitment to Dll1 and that Snx18, which interacts with dynamin 2, modestly regulates Dll1 endocytosis. Furthermore, the ubiquitin ligase activity of Mib1 is induced by Notch ligand-receptor interactions. Mib1 promotes the interaction between dynamin 2 and Snx18 in an ubiquitin ligase activity-dependent manner. These results suggest that Mib1 modulates dynamin recruitment by regulating the interaction between Snx18 and dynamin 2, thereby helping to ensure the efficient signaling activity of Notch ligands.
Notch信号通路调控正常发育和组织稳态。配体内吞作用在Notch信号通路激活中发挥关键作用。诸如epsin和发动蛋白等内吞蛋白通过介导Notch配体内吞作用参与Notch配体活性。泛素连接酶Mib1也通过Notch配体泛素化在Notch信号通路中发挥重要作用。然而，Mib1与内吞蛋白之间的分子联系尚未完全明确。在此，我们表明Mib1参与发动蛋白2募集至Dll1，并且与发动蛋白2相互作用的Snx18适度调节Dll1内吞作用。此外，Mib1的泛素连接酶活性由Notch配体-受体相互作用诱导。Mib1以泛素连接酶活性依赖的方式促进发动蛋白2与Snx18之间的相互作用。这些结果表明，Mib1通过调节Snx18与发动蛋白2之间的相互作用来调控发动蛋白募集，从而有助于确保Notch配体的有效信号活性。
