Exploring New Players in Proteostasis

维持蛋白质稳态，也称为蛋白质稳态，对于所有的过程都是至关重要的。 生物学因此，毫不奇怪，细胞含有一整套分子伴侣和蛋白酶， 其任务是正确折叠和靶向新生蛋白质，防止未经请求的蛋白质错误折叠， 蛋白质对抗不可逆转的聚集。然而，不幸的是， 蛋白质稳态网络的变化确实会发生，而且可能是毁灭性的，特别是在它们与淀粉样蛋白的关系中， 相关的蛋白质折叠疾病，包括阿尔茨海默病和帕金森病。我的实验室专注于两个 不同的机制参与维持蛋白质稳态。我的第一个主要项目集中在 聚磷酸盐是一种高度保守的聚合物，由长链的磷酸- 酸酐键合的磷酸盐。我们实验室以前的工作表明，polyP具有许多共同的特征， 蛋白伴侣，包括其防止应激特异性蛋白质聚集和保护 通过调节疾病相关的淀粉样蛋白原纤维的形成，神经元细胞对抗淀粉样蛋白毒性。最 最近，我们在polyP的压力保护功能中增加了一个新的功能， 液-液相变与核相关蛋白，并在这样做，有助于沉默 基因移动的元素。我们现在将使用多管齐下的细胞生物学，生化学和冷冻- 基于EM的结构方法，以i）理解驱动polyP与蛋白质相互作用的参数， 这些多种不同的能力，ii）测试令人兴奋的假设，基于两个最近解决的cryoEM 通过对患者来源的原纤维的结构的研究，聚P是淀粉样蛋白生成的生理学相关调节剂， 过程，和iii）研究polyP的新确定的作用，作为细菌的关键组成部分， 异染色质我实验室的第二个主要研究方向是基于组蛋白的 表观遗传修饰是一种重要的，但还没有得到充分研究的机制， 蛋白质稳态我们认为这些修饰可以在短期内影响蛋白质稳态， 甚至可能是跨代的。我们将专注于可遗传的组蛋白修饰H3 K4 me 3， 我们和其他人已经证明其整体减少可以增加应激基因表达，改善应激， 抵抗和保护生物体免受淀粉样蛋白相关毒性。我们的主要目标是探索 H3 K4 me 3水平的整体变化如何对蛋白质稳态产生这些相应影响的机制 特别是淀粉样蛋白生成过程。我们的研究有可能增加全新的 层的机制，以调节蛋白质稳态，并将有助于实现总体目标 识别保护蛋白质组的主要参与者并了解它们如何工作。

Maintaining protein homeostasis, also known as proteostasis, is fundamentally important for all processes in biology. It is therefore not surprising, that cells contain an entire fleet of chaperones and proteases, which are tasked to correctly fold and target nascent proteins, prevent unsolicited protein misfolding and protect proteins against irreversible aggregation. Unfortunately, however, disturbances in the activity or composition of the proteostasis network do occur, and can be devastating, particularly in their relationship to amyloid- related protein folding diseases, including Alzheimer’s and Parkinson’s disease. My lab focuses on two different mechanisms that are involved in maintaining protein homeostasis. My first major project centers on the functional activity of polyphosphate, a highly conserved polymer composed of long chains of phospho- anhydride bonded phosphates. Previous work from our lab demonstrated that polyP shares many features with protein chaperones, including its ability to prevent stress-specific protein aggregation, and to protect neuronal cells against amyloid toxicity by modulating disease-associated amyloid fibril formation. Most recently, we added a new function to polyP’s stress-protective repertoire by demonstrating that it undergoes liquid-liquid phase transitions with nucleoid-associated proteins, and in doing so, contributes to the silencing of genetic mobile elements in bacteria. We will now use a multipronged cell biological, biochemical and cryo- EM-based structural approach to i) understand the parameters that drives polyP to interact with proteins in these multiple different capacities, ii) test the exciting hypothesis, based on two recently solved cryoEM structures of patient-derived fibrils, that polyP is a physiologically relevant modulator of amyloidogenic processes, and iii) investigate polyP’s newly identified role as a critical component of bacterial heterochromatin. The second major research arm in my lab is centered on the hypothesis that histone-based epigenetic modifications constitute an important but vastly understudied mechanism that acts in regulating protein homeostasis. We posit that these modifications can affect proteostasis in the short term, long-term and potentially even trans-generationally. We will focus on the inheritable histone modification H3K4me3, whose global reduction has been shown by us and others to increase stress gene expression, improve stress resistance and protect organisms against amyloid-related toxicity. Our major goals are to explore the mechanism of how global changes in H3K4me3 levels can exert these consequential effects on proteostasis in general and amyloidogenic processes in particular. Our studies have the potential of adding entirely new layers of mechanisms to the regulation of protein homeostasis, and will aid in achieving the overarching goal of identifying the major players guarding the proteome and understanding how they work.