Consequences of the metazoan unfolded protein response

点击翻译按钮获取中文摘要

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.