Exploring New Players in Proteostasis

探索蛋白质稳态的新参与者

基本信息

批准号：
10626878
负责人：
Ursula H. Jakob
金额：
$ 71.88万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2027-04-30
项目状态：
未结题

项目摘要

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.

维持蛋白质稳态，也称为蛋白质稳态，对于生物体内的所有过程至关重要。因此，细胞包含一整套分子伴侣和蛋白酶也就不足为奇了。负责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并保护然而不幸的是，蛋白质的活性或组成受到干扰。蛋白质稳态网络的变化确实发生，并且可能是毁灭性的，特别是在它们与淀粉样蛋白的关系方面相关的蛋白质折叠疾病，包括阿尔茨海默病和帕金森病，我的实验室重点研究两种疾病。我的第一个主要项目集中于维持蛋白质稳态的不同机制。聚磷酸盐的功能活性，一种由长链磷酸盐组成的高度保守的聚合物我们实验室之前的工作表明，polyP 有许多共同特征。与蛋白质伴侣，包括其防止应激特异性蛋白质聚集的能力，并保护神经元细胞通过调节与疾病相关的淀粉样蛋白原纤维的形成来对抗淀粉样蛋白毒性。最近，我们通过证明 PolyP 的压力保护功能添加了一个新功能与核相关蛋白的液-液相变，并在此过程中有助于沉默我们现在将使用多管齐下的细胞生物学、生化和冷冻技术。基于 EM 的结构方法 i) 了解驱动 PolyP 与蛋白质相互作用的参数这些多种不同的能力，ii) 基于最近解决的两个冷冻电镜测试令人兴奋的假设患者来源的原纤维的结构，证明 PolyP 是淀粉样蛋白生成的生理相关调节剂过程，以及 iii) 研究 PolyP 新发现的作为细菌关键成分的作用我实验室的第二个主要研究部门集中在基于组蛋白的假设上。表观遗传修饰构成了一种重要但尚未充分研究的机制，其作用是调节我们认为这些修饰可以影响短期和长期的蛋白质稳态。甚至可能是跨代的，我们将重点关注可遗传的组蛋白修饰 H3K4me3，我们和其他人已经证明其全球减少可以增加应激基因表达，改善压力我们的主要目标是探索淀粉样蛋白相关毒性的抵抗力并保护生物体。 H3K4me3 水平的整体变化如何对蛋白质稳态产生这些间接影响的机制一般而言，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内容。调节蛋白质稳态的多层机制，将有助于实现总体目标确定保护蛋白质组的主要参与者并了解它们的工作原理。

项目成果

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Inorganic polyphosphate, a multifunctional polyanionic protein scaffold.

无机聚磷酸盐，一种多功能聚阴离子蛋白质支架。

DOI：
发表时间：
2019-02-08
期刊：
影响因子：
0
作者：
Xie, Lihan;Jakob, Ursula
通讯作者：
Jakob, Ursula

Mechanistic insights into the protective roles of polyphosphate against amyloid cytotoxicity.

多磷酸盐对抗淀粉样蛋白细胞毒性的保护作用的机制见解。

DOI：
发表时间：
2019
期刊：
影响因子：
4.4
作者：
Lempart, Justine;Tse, Eric;Lauer, James A;Ivanova, Magdalena I;Sutter, Alexandra;Yoo, Nicholas;Huettemann, Philipp;Southworth, Daniel;Jakob, Ursula
通讯作者：
Jakob, Ursula

Copper Induces Protein Aggregation, a Toxic Process Compensated by Molecular Chaperones.

铜诱导蛋白质聚集，这是一种由分子伴侣补偿的有毒过程。

DOI：
发表时间：
2022-04-26
期刊：
影响因子：
6.4
作者：
Zuily, Lisa;Lahrach, Nora;Fassler, Rosi;Genest, Olivier;Faller, Peter;Sénèque, Olivier;Denis, Yann;Castanié;Genevaux, Pierre;Jakob, Ursula;Reichmann, Dana;Giudici;Ilbert, Marianne
通讯作者：
Ilbert, Marianne

Early life changes in histone landscape protect against age-associated amyloid toxicities through HSF-1-dependent regulation of lipid metabolism.

生命早期组蛋白景观的变化通过 HSF-1 依赖性脂质代谢调节来防止与年龄相关的淀粉样蛋白毒性。

DOI：
发表时间：
2024-01
期刊：
影响因子：
0
作者：
Oleson, Bryndon J;Bhattrai, Janakraj;Zalubas, Sarah L;Kravchenko, Tessa R;Ji, Yuanyuan;Jiang, Emily L;Lu, Christine C;Madden, Ciara R;Coffman, Julia G;Bazopoulou, Daphne;Jones, Jace W;Jakob, Ursula
通讯作者：
Jakob, Ursula

Polyphosphate Stabilizes Protein Unfolding Intermediates as Soluble Amyloid-like Oligomers.

多磷酸盐以可溶性淀粉样蛋白样低聚物的形式稳定蛋白质解折叠中间体。

DOI：
发表时间：
2018
期刊：
影响因子：
5.6
作者：
Yoo, Nicholas G;Dogra, Siddhant;Meinen, Ben A;Tse, Eric;Haefliger, Janine;Southworth, Daniel R;Gray, Michael J;Dahl, Jan;Jakob, Ursula
通讯作者：
Jakob, Ursula