Novel role of an aquaporin in endosome biogenesis and Notch signaling

Notch信号传导需要受体及其配体的内吞作用， 内部化Notch的路由对于信号传输和再循环都有影响 和未激活受体的降解。我们发现一种典型的果蝇 一种称为大脑（bib）的突变体在Notch的内体积累方面表现出明显的缺陷 和其他表面衍生的蛋白质。Bib蛋白具有N-末端结构域， 与哺乳动物水通道蛋白高度同源，其转运水、离子和其它小分子物质， 溶质穿过生物膜。利用细胞生物学和遗传学方法，我们有 确定Bib对于早期内体的成熟和适当的膜是必不可少的 Notch在内体途径中的运输。在没有Bib功能的情况下，内体是 主要是在早期内陷阶段和形成酸化溶酶体 细胞器受损。这些影响伴随着异常的亚细胞运输， 由β-分泌酶切割产生的细胞内Notch片段， 强调Notch膜运输对于有效信号转导的重要性。 该项目揭示了细胞器中水通道蛋白家族成员的新功能 内体-溶酶体运输途径内的生物发生，我们最初的研究是 最近发表在Cell（Kanwar和Fortini，2008）上。我们未来的计划包括搜索 Bib相互作用的蛋白质，以及对Bib与其他蛋白质之间关系的更详细研究。 内体运输因子。

Notch signaling requires endocytosis of both the receptor and its ligand, and endosomal routing of internalized Notch has implications for signal transmission as well as recycling and degradation of unactivated receptors. We have discovered that a classical Drosophila mutant termed big brain (bib) exhibits striking defects in the endosomal accumulation of Notch and other surface-derived proteins. The Bib protein possesses an N-terminal domain that is highly homologous to mammalian aquaporins, which transport water, ions, and other small solutes across biological membranes. Using cell biological and genetic approaches, we have determined that Bib is essential for the maturation of early endosomes and the proper membrane trafficking of Notch in the endosomal pathway. In the absence of Bib function, endosomes are arrested primarily at an early invaginating stage and the formation of acidified lysosomal organelles is impaired. These effects are accompanied by aberrant subcellular trafficking of the intracellular Notch fragment produced by γ-secretase cleavage, emphasizing the importance of Notch membrane trafficking for efficient signal transduction. This project has uncovered a novel function for an aquaporin family member in organelle biogenesis within the endosome-lysosome trafficking route, and our initial studies were published recently in Cell (Kanwar and Fortini, 2008). Our future plans include searches for Bib-interacting proteins, and more detailed studies on the relationship of Bib to other endosomal trafficking factors.