Regulation of intracellular protein traffic

描述(由申请人提供)：将蛋白质定位到酵母的溶酶体样空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，将它们包装成运输小泡，并通过泡前内体隔间将它们输送到空泡。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，我们转向了大量酵母突变株，这些突变株在向液泡输送蛋白质方面存在缺陷。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，该机制是将蛋白质从高尔基体晚期隔间分选到液泡所必需的。这里描述的研究集中在空泡蛋白定位系统的一个事件上，即囊泡介导的空泡蛋白从高尔基体分拣隔室到泡前内小体的传递。这一运输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转移到内体。这些受体在细胞内的运输是调节通过空泡蛋白分选途径的流量的关键点。在哺乳动物细胞中，这种分选途径的重要性被严重的溶酶体储存疾病(例如i-细胞病)以及其他疾病(例如骨质疏松症和某些类型的癌症的进展)所例证，这些疾病是由溶酶体水解酶的错误定位引起的或与其相关。这项研究的长期目标是以酵母空泡蛋白分选途径为模型系统，了解参与这一递送过程的潜在机制。

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.