Regulation of intracellular protein traffic

描述（由申请人提供）：蛋白质定位于酵母（酿酒酵母）的溶酶体样液泡是一个复杂的过程。独特的细胞成分必须识别液泡蛋白，将它们从分泌蛋白中分离出来，将它们包装到运输小泡中，并通过前液泡内体区室将它们运送到液泡中。我们研究的长期目标是揭示参与这一传递过程的潜在分子机制。为此，我们已经转向了大量的酵母突变体，这些突变体在蛋白质递送到液泡方面有缺陷。在这些vps突变体中受影响的基因产物可能是反式作用细胞机制的一部分，这是从晚期高尔基体隔室到液泡的蛋白质分选所需的。这里描述的研究集中在一个事件的液泡蛋白定位系统，囊泡介导的传递液泡蛋白从高尔基体分选室的prevacuolar内体。这个转运步骤涉及大量的蛋白质，这些蛋白质将与货物结合的液泡蛋白受体从高尔基体移动到内体。这些受体的细胞内运输是调节通过液泡蛋白分选途径的通量的关键点。在哺乳动物细胞中，这种分选途径的重要性通过严重的溶酶体贮积病（例如I细胞病）以及由溶酶体水解酶的错误定位引起或与溶酶体水解酶的错误定位相关的其他疾病（例如骨质疏松症和某些类型的癌症的进展）来举例说明。本研究的长期目标是以酵母空泡蛋白分选途径为模型系统，了解这一传递过程中所涉及的潜在机制。

DESCRIPTION (provided by applicant): The localization of proteins to the lysosome-like vacuole of the yeast, Saccharomyces cerevisiae, Is a complex process. Unique cellular components must recognize vacuolar proteins, sort them away from secretory proteins, package them into transport vesicles and deliver them to the vacuole via a prevacuolar endosomal compartment. The long term goal of our research is to uncover the underlying molecular mechanisms that are involved in this delivery process. Toward this end, we have turned to the large set of yeast mutants that are defective in protein delivery to the vacuole. The gene products affected in these vps mutants are likely part of the trans-acting cellular machinery that is required for sorting of proteins from a late Golgi compartment to the vacuole. The studies described here focus on one event of the vacuolar protein localization system, the vesicle-mediated delivery of vacuolar proteins from the Golgi sorting compartment to the prevacuolar endosome. This transport step involves a large number of proteins that move vacuolar protein receptors bound with cargo from the Golgi to the endosome. The intracellular trafficking of these receptors are a key point at which flux through the vacuolar protein-sorting pathway is regulated. In mammalain cells, the importance of this sorting pathway is exemplified by the serious lysosomal storage diseases (e.g. I-cell disease) as well as other diseases (e.g. osteoporosis and the progression of certain types of cancer) that result from or are correlated with the mislocalization of lysosomal hydrolases. The long-term goal of this research is to understand the underlying mechanisms that are involved in this delivery process using the yeast vacuolar protein sorting pathway as a model system.