J proteins direct the processing of misfolded proteins within cellular protein quality control

所有的蛋白质都需要获得它们定义的三维构象才能正常工作，这一过程被称为蛋白质折叠。蛋白质折叠可以受到许多环境和基因攻击的挑战，导致错误折叠的蛋白质，通常是功能失调的，往往对细胞有毒。因此，细胞蛋白质质量控制，即所有涉及蛋白质合成、维持和降解的机制，已经在所有活细胞中进化，以保护细胞免受蛋白质错误折叠的有害后果。J蛋白类分子伴侣在细胞蛋白质质量控制中起着关键作用，因为它们促进适当的蛋白质合成、维持和降解。J蛋白是分子伴侣中种类最多的一类，因为到目前为止所分析的所有生物体中不同J蛋白的数量超过了所有其他分子伴侣的数量。这种令人困惑的多样性意味着J蛋白进化为选择性地靶向客户蛋白，并在细胞蛋白质量控制网络中执行特殊功能。然而，支撑这种靶标特异性的分子和细胞机制以及单个J蛋白的独特细胞功能仍不清楚。我们在此提出的研究计划旨在通过结合遗传学，系统生物学，细胞生物学和计算方法，以酵母（Saccharomyces*cerevisiae）作为遗传可处理的模式生物，确定J蛋白的靶特异性和不同的细胞作用。我们的研究将确定J蛋白指定细胞蛋白质量控制活性的一般生物学原理，从而在活细胞中执行功能独特的角色。****

**All proteins need to*acquire their defined three-dimensional conformation in order to function*properly, a process termed protein folding. Protein folding can be challenged*by numerous environmental and genetic assaults resulting in misfolded proteins*that are usually dysfunctional and often toxic to the cell. Cellular protein*quality control, i.e. all mechanisms involved in protein synthesis,*maintenance, and degradation, has thus evolved in all living cells to protect*cells from the detrimental consequences of protein misfolding. Molecular*chaperones of the J protein class are key players in cellular protein quality*control as they facilitate proper protein synthesis, maintenance, and*degradation. J proteins constitute the most diverse class of molecular chaperones as the*number of different J proteins in all organism that have been analyzed so far*exceeds the number of all other molecular chaperone. This perplexing diversity*implies that J proteins evolved to selectively target client proteins and*execute specialized functions within the cellular protein quality control*network. Yet the molecular and cellular mechanisms underpinning this target specificity*and the distinct cellular functions of individual J proteins remain unclear. Our*research program proposed here aims to determine the target specificity and*distinct cellular roles of J proteins by applying a combination of genetic,*systems biology, cell biological and computational approaches using yeast (Saccharomyces*cerevisiae) as a genetically tractable model organism. Our research will*determine general biological principles by which J proteins specify the*activity of cellular protein quality control and thus execute functionally*distinct roles in living cells.****