Consequences of the metazoan unfolded protein response

描述(申请人提供)：未折叠蛋白反应(UPR)，最初被认为是与内质网(ER)中未折叠蛋白积累有关的应激反应，已被证明在后生动物的发育和专门分泌细胞的分化中发挥关键作用。UPR在酵母中的特性最好，在酵母中，一条简单的线性途径激活与分泌蛋白的折叠和降解有关的基因的转录。然而，在rnetazoans中发现的额外成分表明，高等真核生物中的UPR更加复杂，涉及几个平行的途径，并影响转录和翻译。然而，人们对各个组成部分如何履行其扩展的功能仍知之甚少。通过本文描述的研究，我们希望通过确定UPR在后生动物中的转录范围，破译涉及的平行反应元件的差异效应，并从功能上分析反应的靶点，重点研究UPR与未能正确折叠或寡聚的分泌蛋白的内质网相关降解(ERAD)之间的关系，从而深入了解这一过程。我们还计划测试关于反应的不同元素的时间协调以及细胞区分末端错误折叠和过度丰富的蛋白质的能力的具体假设。

DESCRIPTION (provided by applicant): The unfolded protein response (UPR), originally identified as a stress response associated with the accumulation of unfolded proteins in the endoplasmic reticulum (ER), has been shown to play a key role in development of metazoans and in differentiation of cells specializing in secretion. The UPR is best characterized in yeast, where a simple linear pathway activates the transcription of genes involved in the folding and degradation of secreted proteins. The discovery of additional components in rnetazoans, however, has shown that the UPR in higher eukaryotes is more complex, involving several parallel pathways and affecting both transcription and translation. How the individual components carry out their expanded function, however, remains poorly understood. Through the research described here, we hope to gain insight into this process by determining the transcriptional scope of the UPR in metazoans, deciphering the differential effects of the parallel response elements involved, and functionally analyzing the targets of the response, focusing on the relationship between the UPR and ER-associated degradation (ERAD) of secreted proteins that fail to fold or oligomerize properly. We also plan to test specific hypotheses regarding the coordination of the timing of different elements of the response and the ability of the cell to distinguish between terminally misfolded vs. overly abundant proteins.