Consequences of the metazoan unfolded protein response

描述（由申请人提供）：未折叠蛋白反应（UPR）最初被鉴定为与内质网（ER）中未折叠蛋白积累相关的应激反应，已显示在后生动物发育和分泌细胞分化中起关键作用。UPR在酵母中最具特征，其中简单的线性途径激活参与分泌蛋白质折叠和降解的基因的转录。然而，在介体动物中发现的其他组分表明，高等真核生物中的UPR更为复杂，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发挥其扩大的功能仍然知之甚少。通过这里描述的研究，我们希望通过确定后生动物中UPR的转录范围，破译所涉及的平行响应元件的差异效应，并在功能上分析响应的靶点，重点关注UPR和ER相关降解（ERAD）分泌蛋白未能正确折叠或寡聚化之间的关系，来深入了解这一过程。我们还计划测试关于不同响应元素的时间协调以及细胞区分末端错误折叠与过度丰富蛋白质的能力的特定假设。

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.