Unfolded protein response in the model species Arabidopsis thaliana

 描述(由申请人提供)：内质网(ER)中的蛋白质合成在应激条件下可以显著上调。为了避免蛋白质转位和折叠的堵塞，内质网感知这种应激条件的早期指标，并以所谓的未折叠蛋白质反应(UPR)做出反应。这是一个古老的信号转导途径，导致内质网伴侣和其他折叠因子的快速补充，并在致力于细胞凋亡之前避免需要能量的修复机制。UPR对于维持细胞的生长和发育以及抗击疾病和非生物胁迫至关重要。有趣的是，UPR的疗效在同一物种的个体之间差异很大，但潜在的分子原因尚不清楚。为了启动UPR，酵母在很大程度上依赖于保守的内质网应激传感器Ire1p的作用。在进化过程中，UPR传感器套件已经扩展，以适应多细胞环境中更具体的反应。从体外研究和细胞培养分析中可以了解内质网应激传感器的基本激活机制和一般功能。然而，普遍定期审议的监管机构如何协调工作，以最低的能源成本维持细胞的健康生长和发展尚不清楚。我们希望在拟南芥中解决这个基本问题，因为植物和后生动物UPR的保护，这个模式物种的遗传多样性和基因组学资源的广泛可用，以及植物界作为可再生能源、食物和材料的来源的相关性。这项建议的近期目标是1)利用具有广泛遗传多样性的自然种群来确定物种内UPR可变性的分子决定因素，2)了解体内各种UPR途径之间的动态平衡控制机制，3)定义调节完整生物体内ER应激反应的非常规机制。为了实现我们的目标，我们将继续我们的全基因组研究，以表征UPR的多样性，以及我们的功能基因组学分析，以确定体内UPR信号通路的动态平衡机制。我们还将使用先进的下一代测序策略来定义UPR的转录后调控。我们的结果将使我们对复杂多细胞生物体中内质网应激过程中UPR信号网络的复杂性有一个广泛而深入的理解。将植物作为研究复杂生物体中UPR的进化上不同和易于处理的模型也很重要，因为它将允许比较植物、酵母和动物的UPR，因此将提供对这些系统的重要见解，增加真核细胞生物学的基础知识。我们的成果不仅将增强我们对人类生长和疾病的了解，还将使我们能够在易于处理的多细胞模型中开发药物，并有助于我们了解农业过程中的限制因素和旨在维持地球粮食安全的植物生物技术。

 DESCRIPTION (provided by applicant): Protein synthesis in the endoplasmic reticulum (ER) can be dramatically upregulated under stress conditions. To avoid jamming of protein translocation and folding, the ER senses early indicators of such stress conditions and responds with the so-called unfolded protein response (UPR). This is an ancient signal transduction pathway that leads to the rapid replenishment of ER chaperones and other folding factors and avoids energy- requiring repair mechanisms before committing to apoptosis. The UPR is critical to sustain cell growth and development and to combat disease and abiotic stress. Interestingly, the efficacy of the UPR varies largely among individuals of the same species, but the underlying molecular causes are unknown. To initiate the UPR, yeast relies heavily on the action of a conserved ER stress sensor, Ire1p. During the course of evolution, the suite of UPR sensors has expanded to accommodate more specific responses in a multicellular context. The basic activation mechanisms and general function of the ER stress sensors are largely known from in vitro studies and cell culture analyses. However, how the UPR regulators work coordinately to sustain healthy cell growth and development with a minimum of energy costs is unknown. We wish to address this fundamental question in Arabidopsis thaliana, because of the conservation of plant and metazoan UPRs, the vast availability of genetic diversity and genomics resources for this model species, and the relevance of the plant kingdom as a source for renewable energy, food, and materials. The immediate goals of this proposal are 1) to define the molecular determinants underlying intra-specific UPR variability using natural populations with broad genetic diversity, 2) to understand the mechanisms that control homeostasis among the various UPR pathways in vivo, and 3) to define non-conventional mechanisms that modulate ER stress responses in intact organisms. To achieve our goals, we will pursue our genome-wide studies to characterize UPR diversity as well as our functional genomics analyses to define the mechanisms for homeostasis of the UPR signaling pathways in vivo. We will also use advanced next-generation sequencing strategies to define post-transcriptional modulation of the UPR. Our results will lead to a broad and deep understanding of the complexity of the UPR signaling network during ER stress in the context of complex multicellular organisms. Adding plants as an evolutionarily distinct and tractable model for the study of the UPR in complex organisms is also important because it will allow comparing and contrasting plant, yeast, and animal UPRs, and thus will provide significant insights into these systems, adding to the fundamental knowledge of eukaryotic cell biology at large. Our results will not only enhance our understanding of human growth and disease, they will also permit the development of drugs in a tractable multicellular model, and contribute to our knowledge of limiting factors in agricultural processes and plant biotechnology designed to sustain food security on earth.