Unfolded protein response in the model species Arabidopsis thaliana

模式物种拟南芥中未折叠的蛋白质反应

• 批准号: 8463002
• 负责人: Federica Brandizzi
• 金额: $ 27.7万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8463002
• 关键词: Address; Adopted; Affect; Agriculture; Animals; Arabidopsis; Biological; Biological Assay; Biological Models; Biosensor; Biotechnology; Cell Differentiation process; Cell Line; Cells; Cellular biology; Characteristics; Dependency; Development; Disease; Embryo; Endoplasmic Reticulum; Eukaryota; Eukaryotic Cell; Evolution; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Transcription; Genomics; Goals; Growth; Growth and Development function; Health; Heterotrimeric GTP-Binding Proteins; Homeostasis; Human; In Vitro; Knowledge; Lead; Learning; Link; Mammals; Maps; Mediating; Mediator of activation protein; Membrane; Modeling; Molecular; Molecular Genetics; Mouse-ear Cress; Organ Model; Organism; Output; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Plant Model; Plant Roots; Plants; Play; Process; Protein Biosynthesis; Proteins; Research; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Staging; Stimulus; Stress; Study models; System; Transducers; Yeasts; arm; base; biological adaptation to stress; cell growth; coping; design; endoplasmic reticulum stress; experimental analysis; food security; functional genomics; human disease; improved; in vitro Assay; in vivo; innovation; insight; loss of function mutation; mutant; novel; plant growth/development; protein complex; response; secretory protein; sensor; tool; transcription factor; transcriptomics

DESCRIPTION (provided by applicant): Adverse environmental conditions as well as physiological situations requiring enhanced secretory protein synthesis can cause an imbalance between demand and capacity of protein synthesis at the endoplasmic reticulum (ER). The ER can sense stress and restore homeostasis by invoking a protective signaling pathway known as the unfolded protein response (UPR). To initiate UPR, yeast largely relies on a linear arm based on the action of a conserved sensor, Ire1p. During the course of evolution, the suite of UPR arms harnessed additional sensors to accommodate more specific responses in a multicellular context. A major challenge in UPR studies is now to understand the biological role of the various UPR arms in intact organisms to define how the UPR signaling network functions to direct diverse cell-fate decisions in development and response to biotic and abiotic stress. The conservation of plant and metazoan UPR and the availability of powerful genomics and molecular tools render the model plant Arabidopsis thaliana an appealing system in which to address these questions. In plants, the UPR is thought to play a major role in various stress situations, but the understanding of plant UPR mechanisms is still limited. In Arabidopsis, two membrane-tethered blip transcription factors, bZIP28 and bZIP60, and a subunit of the conserved heterotrimeric G protein complex, AGB1, have been shown to function as regulators of plant UPR, but little is known about the molecular components of the UPR arms controlled by these mediators. We have recently established a direct involvement of AtIRE1 in ER stress response and in growth. These findings will enable us to explore the role of IRE1 in combination with other key players of plant UPR to develop a model that links UPR signaling during stress responses with growth and development in vivo in a multicellular context. The immediate goals of this proposal therefore are 1) to elucidate conserved and plant-specific features in the signal transduction pathway controlled by AtIRE1; 2) to define the role of the UPR arms in growth, development, and various conditions of stress; and 3) to identify the target genes corresponding to each UPR arm to define downstream effectors and to elucidate how the UPR signaling arms intersect with each other. Adding plants as an evolutionarily distinct and tractable model for the study of the UPR in multicellular organisms is important because it will allow comparing and contrasting plant, yeast, and animal UPRs, and thus will provide significant insights into these systems, adding to our fundamental understanding of eukaryotic cell biology at large. To achieve our goals we will integrate functional genomics with in vitro assays and transcriptomics. We will be able to establish how plants depend on the UPR signaling network during growth and development and in response to stress conditions that require enhanced secretory protein synthesis. Our results will not only enhance our understanding of human growth and disease, they will also permit the development of UPR drugs in a tractable multicellular model, and contribute to our understanding of limiting factors in agricultural processes and plant biotechnology designed to sustain food security on earth.

描述（由申请人提供）：不利的环境条件以及需要增强分泌蛋白质合成的生理情况可能会导致内质网（ER）蛋白质合成的需求和能力之间的不平衡。 ER可以通过调用称为展开的蛋白质反应（UPR）的保护性信号传导途径来感知压力并恢复稳态。为了启动UPR，酵母在很大程度上基于保守传感器IRE1P的作用依赖于线性臂。在进化过程中，UPR武器的套件利用了其他传感器，以在多细胞环境中适应更具体的响应。现在，UPR研究的主要挑战是了解各种UPR臂在完整生物体中的生物学作用，以定义UPR信号网络如何在开发和对生物和非生物胁迫的反应中指导各种细胞命运决策。植物和后生UPR的保护以及强大的基因组学和分子工具的可用性使模型植物拟南芥成为一个吸引人的系统，可以在其中解决这些问题。在植物中，UPR被认为在各种压力情况下都起着重要作用，但是对植物UPR机制的理解仍然有限。在拟南芥中，两个膜束缚的BLIP转录因子BZIP28和BZIP60和保守的异三聚体G蛋白复合物AGB1的亚基AGB1被证明是植物UPR的调节剂，但对这些媒体控制的UPR武器的分子成分知之甚少。我们最近已经建立了Atire1参与ER应力反应和生长的直接参与。这些发现将使我们能够探索IRE1与工厂UPR的其他关键参与者结合使用的作用，以开发一种模型，该模型将压力反应期间的UPR信号与多细胞环境中的体内生长和发展联系起来。因此，该提案的直接目标是1）阐明由Atire1控制的信号转导途径中的保守和植物特异性特征； 2）定义UPR臂在生长，发育和各种压力条件中的作用； 3）要识别与每个UPR臂相对应的目标基因，以定义下游效应子并阐明UPR信号臂如何相互相交。将植物作为一种在多细胞生物中进行UPR的进化不同的植物模型添加很重要，因为它将允许比较和对比植物，酵母和动物UPR，因此将对这些系统提供重要的见解，从而增加了我们对真核细胞生物学的基本了解。为了实现我们的目标，我们将将功能基因组学与体外测定和转录组学相结合。我们将能够确定植物在生长和发展过程中如何依赖UPR信号网络，并响应需要增强分泌蛋白质合成的压力条件。我们的结果不仅将增强我们对人类生长和疾病的理解，还将允许在可探讨的多细胞模型中开发UPR药物，并有助于我们对农业过程中限制因素的理解和旨在维持地球粮食安全的植物生物技术的理解。