Novel role of an aquaporin in endosome biogenesis and Notch signaling

Notch信号需要受体及其配体的内吞作用，内化Notch的内体路径对信号传递以及未激活受体的回收和降解具有影响。我们已经发现一个被称为big brain （bib）的经典果蝇突变体在Notch和其他表面衍生蛋白的内体积累中表现出惊人的缺陷。Bib蛋白具有一个与哺乳动物水通道蛋白高度同源的n端结构域，水通道蛋白通过生物膜运输水、离子和其他小溶质。利用细胞生物学和遗传学方法，我们已经确定Bib对于早期核内体的成熟和Notch在核内体途径中适当的膜运输是必不可少的。在没有Bib功能的情况下，核内体主要在早期内陷阶段被阻止，酸化溶酶体细胞器的形成受到损害。这些影响伴随着细胞内Notch片段的异常亚细胞运输。-分泌酶裂解，强调Notch膜运输对有效信号转导的重要性。该项目揭示了水通道蛋白家族成员在胞内体-溶酶体运输路线中细胞器生物发生中的新功能，我们的初步研究最近发表在Cell上（Kanwar和Fortini， 2008）。我们未来的计划包括寻找Bib相互作用蛋白，并更详细地研究Bib与其他内体运输因子的关系。

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.