Ubiquitin-dependent sorting in endosomes and the TGN

描述（由申请人提供）：将膜蛋白分选到后期内体形成的腔内囊泡中是调节许多生物途径的基本过程，这些途径依赖于维持一组给定的细胞表面膜蛋白的适当水平。这是指导溶酶体中蛋白质的传递和降解的途径。这一途径是由泛素驱动的，泛素在附着在膜蛋白货物上时作为分选信号起作用。这一过程控制着几乎所有细胞表面膜蛋白的降解，了解这一降解过程具有重要意义，因为它影响了一系列依赖于特定膜蛋白（如细胞表面的转运蛋白和信号受体）适当活性的正常和致病过程。竞争性更新提案的长期目标是了解这种泛素依赖的分类途径是如何被控制的，并将深入了解当这一过程出错时，癌症等疾病状态是如何实现的。为了实现这一目标，我们设计了以下目标：1)发现Nedd4相关泛素连接酶的主要家族如何被编程以靶向不同的细胞表面膜蛋白；2)发现泛素化膜蛋白如何被内体分选机制识别，以及该货物如何在组织分选装置本身中发挥积极作用；3)利用一系列基因筛选发现参与腔内囊泡形成过程的新蛋白质。

DESCRIPTION (provided by applicant): Sorting membrane proteins into intralumenal vesicles that form within late endosomes is a fundamental process that regulates many biological pathways that rely on maintaining appropriate levels of a given set of cell surface membrane proteins. This is the pathway that guides the delivery and degradation of proteins in lysosomes. This pathway is driven by ubiquitin, which works as a sorting signal when attached to membrane protein cargo. This process controls the degradation of almost all cell surface membrane proteins and understanding this degradative process is significant since it impacts a wide array of normal and pathogenic processes that rely on proper activity of particular membrane proteins such as transporters and signaling receptors at the cell surface. The long-term goal of the competitive renewal proposal is to understand how this ubiquitin-dependent sorting pathway is controlled, and will lead to insights into how disease states such as cancer might be achieved when this process goes awry. To accomplish this we have devised aims to 1) discover how the major family of Nedd4- related ubiquitin ligases are programed to target different cell surface membrane proteins; 2) discover how ubiquitinated membrane proteins are recognized by the endosomal sorting machinery and how that cargo plays an active role in organizing the sorting apparatus itself; and 3) discover new proteins that participate in the process of intralumenal vesicle formation using a series of genetic screens.