Regulation of intracellular protein traffic

描述（由申请人提供）：将蛋白质定位到酵母（Saccharomyces cerevisiae）的溶酶体样液泡中是一个复杂的过程。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，将它们包装成运输囊泡，并通过泡前内体腔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，我们研究了大量的酵母突变体，这些突变体在向液泡输送蛋白质方面存在缺陷。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，这种机制是将蛋白质从晚期高尔基腔室分选到液泡所必需的。本文所描述的研究集中于液泡蛋白定位系统的一个事件，即液泡蛋白从高尔基分选室到泡前内体的囊泡介导递送。这一转运步骤涉及大量蛋白质将与货物结合的空泡蛋白受体从高尔基体转移到核内体。这些受体的细胞内运输是通过空泡蛋白分选途径调节通量的关键点。在哺乳动物细胞中，严重的溶酶体贮积病（如i细胞病）以及其他疾病（如骨质疏松症和某些类型的癌症进展）都是由溶酶体水解酶定位错误引起的，或与溶酶体水解酶定位错误有关，这就证明了这种分选途径的重要性。本研究的长期目标是利用酵母液泡蛋白分选途径作为模型系统，了解参与这一传递过程的潜在机制。

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.