Hsp110 protein chaperone function in yeast

描述（由申请人提供）：热休克蛋白（Hsps）在细胞生物学中起双重作用；它们是抵御细胞毒性应激的第一道防线，并且在正常生长条件下紧密地整合到信号传导和调节途径中。热休克蛋白的一个子集，包括Hsp70和Hsp90，作为分子伴侣，可能在底物蛋白生命周期的多个阶段都需要，从生物发生、定位、稳定到激活和降解。蛋白伴侣蛋白在许多病理生理条件下被诱导，包括缺血和肿瘤发生，并且已知可以促进癌蛋白（如v-src激酶和p53肿瘤抑制因子）的稳定性和活性。Hsp110类伴侣蛋白是一种鲜为人知的Hsp70亲缘蛋白，存在于所有真核生物中，在人类中具有未知功能的组织特异性同型。烘焙酵母Hsp110同源物由SSE1和SSE2基因编码，对其功能知之甚少。本研究旨在通过提出三个具体问题来开始理解Hsp110伴侣的细胞作用：1)Sse1如何与酵母Hsp70 Ssa1合作，2)Sse1如何与伴侣Hsp90合作，通过酵母细胞完整性途径参与信号转导，以及3)Sse1如何通过与基本转录复合体Mediator相互作用而独立于Hsp90发挥作用。这些在酵母中进行的特定研究将作为预测Hsp110在哺乳动物细胞中可能促进哪些过程的模型。

DESCRIPTION (provided by applicant): Heat shock proteins (Hsps) play dual roles in cellular biology; they are the first line of defense against cytotoxic stresses, and are tightly integrated into signaling and regulatory pathways under normal growth conditions. A subset of Hsps, including Hsp70 and Hsp90, act as molecular chaperones, and may be required at multiple stages during a substrate protein's lifetime, ranging from biogenesis, localization, and stability, to activation and degradation. Protein chaperones are induced during numerous pathophysiological conditions including ischemia and tumorigenesis, and are known to facilitate stability and activity of oncoproteins such as v-src kinase and the p53 tumor suppressor. The Hsp110 class of chaperones is a poorly understood Hsp70 relative and is present in all eukaryotes, with tissue-specific isoforms of unknown function in humans. The baker's yeast Hsp110 homolog is encoded by the SSE1 and SSE2 genes, and little is known about their function. This proposal seeks to begin to understand the cellular roles of Hsp110 chaperones by asking three specific questions: 1) How does Sse1 operate in partnership with the yeast Hsp70 Ssa1, 2) How does Sse1 participate in signal transduction through the yeast cell integrity pathway in collaboration with the chaperone Hsp90, and 3) How does Sse1 function independently of Hsp90 through interaction with the essential transcriptional complex Mediator? These specific lines of investigation in yeast will serve as a model for predicting which processes Hsp110 may facilitate in mammalian cells.