Unfolded protein response in the model species Arabidopsis thaliana

内质网(ER)中的蛋白质折叠对于细胞的生命是不可或缺的，并不断地改变细胞内的蛋白质结构。 由于生理需求和环境压力而延长。当ER蛋白折叠的动态平衡是 心烦意乱时，一种被称为内质网应激的潜在致命条件被点燃。为了缓解内质网压力，一系列的控制措施。 提供服务的ER膜相关传感器优先生产ER折叠酶和慢性处置 错误折叠的蛋白质。当这些适应性反应不足时，UPR激活促进细胞死亡的过程- 艾斯。由于其关键的家务管理作用，UPR在多细胞生物体的生长和 营养不足会导致对人类有害的疾病，包括糖尿病、神经变性和癌症。 几十年来，人们主要在体外、单细胞模型生物和分化细胞中对UPR进行研究 能够经受住UPR不足或无法概括整个多细胞的复杂性的细胞系 有机体。正因为如此，针对UPR相关疾病的有效医疗疗法的设计将重新 寻求全身UPR模型，在该模型中可以从机制上理解 普遍定期审议在增长、抗压和支持死亡方面的决定。 我的长期研究目标是开发一种进化上独特的模式系统，具有独特的优势 在全身范围内揭示普遍定期审议，以全面理解这一重要标志-- 体内NALING途径。为了实现这一目标，我们的研究解决了普遍定期审议的基本知识差距 植物模式物种拟南芥，由于植物和后生动物UPR和 我们开发并利用了大量的遗传学和基因组学资源来整体研究普遍定期审议- 身体环境。展望未来，我们将建立在我们令人兴奋的新发现的基础上，这些发现支持 在生长和胁迫中依赖于保守的UPR传感器的新的信号转导途径 作为新发现的内质网应激相关细胞死亡的效应因子，在体内不可分辨的内质网应激条件下。 具体地说，我们将集中在1)蛋白质磷酸化的作用取决于最保守的 UPR传感器，蛋白激酶和核糖核酸酶IRE1，在生长和内质网应激缓解中的作用；2)特性- 通过全身正向遗传学发现的新的非冗余细胞死亡效应的具体化 筛选，以及3)保守的UPR独特信号转导途径的机制 转录因子。这些努力将1)定义调节内质网应激的新的非常规机制 反应；2)确定与未解决的内质网应激存活相关的关键细胞命运效应因子 Vivo，以及3)拓展了对UPR信号转导的理解前沿 在全身系统中运行的生物路径。从长远来看，我们的研究将有助于 在细胞水平上了解UPR，并极大地促进我们对体内UPR的理解，因此 克服制定有效疗法以改善与普遍定期审议有关的人类状况方面的瓶颈。

Protein folding in the endoplasmic reticulum (ER) is indispensable for the life of the cell and constantly chal- lenged by physiological demands and environmental stressors. When the homeostasis of ER protein folding is perturbed, a potentially lethal condition, known as ER stress, is ignited. To mitigate ER stress, a set of con- served ER membrane-associated sensors prioritizes the production of ER foldases and disposal of chronically misfolded proteins. When these adaptive responses are insufficient, the UPR activates pro-cell death process- es. Due to its critical housekeeping roles, the UPR is essential during growth of multicellular organisms and insufficiency leads to harmful conditions in humans, including diabetes, neurodegeneration, and cancer. For decades the UPR has been studied mainly in vitro, in unicellular model organisms and in differentiated cell lines, which can survive UPR insufficiency or are unable to recapitulate the complexity of whole multicellular organisms. Because of this, the design of effective medical therapies targeting UPR-associated diseases re- quires whole-body UPR models where it is possible to develop a mechanistic understanding of the impact of the UPR in growth, stress resistance and pro-death decisions. My long-term research goal is to develop an evolutionarily distinct model system with unique advantages for uncovering the UPR in a whole-body context to formulate a comprehensive understanding of this essential sig- naling pathway in vivo. Towards this goal, our research addresses fundamental knowledge gaps of the UPR in the plant model species Arabidopsis thaliana, because of the conservation of plant and metazoan UPRs and the vast genetics and genomics resources that we have developed and leveraged to study the UPR in whole- body context. Moving forward, we will build upon our exciting new findings, which support the existence of novel signal transduction pathways depending upon the conserved UPR sensors in growth and stress, as well as newly identified effectors of ER stress-related cell death in conditions of unresolvable ER stress in vivo. Specifically, we will focus on 1) the role of protein phosphorylation changes depending on the most conserved UPR sensor, the protein kinase and ribonuclease IRE1, in growth and ER stress mitigation; 2) the characteri- zation of novel non-redundant effectors of cell death discovered through a whole-body forward genetics screen, and 3) the mechanisms which underlie the unique signal transduction pathways of the conserved UPR transcription factors. These efforts will 1) define new non-conventional mechanisms that modulate ER stress response; 2) identify critical cell fate effectors with a functional relevance for unresolved ER stress survival in vivo, and 3) expand the frontiers of the understanding of UPR signal transduction at the intersection with other biological pathways operating in a whole-body system. In the long term, our research will contribute to the knowledge of the UPR at the cellular level and significantly advance our understanding of the UPR in vivo, thus overcoming bottlenecks in formulating effective therapeutics to ameliorate human conditions linked to the UPR.