Glucose Signaling in Plants

描述（由申请人提供）：葡萄糖是一种古老的中心信号分子，存在于从大肠杆菌、酵母到植物和人类的广泛生物体中。尽管葡萄糖在基因表达、生理、代谢、细胞增殖和死亡、生长和发育以及人类疾病中发挥着重要作用，但在植物和动物中，葡萄糖信号传导的分子和细胞机制仍然难以捉摸。我们在模式植物拟南芥中的研究提供了令人信服的遗传和生化证据，证明己糖激酶1 （HXK1）是一种进化上保守的葡萄糖传感器，它整合了营养和激素信号，以控制基因表达和植物生长，以响应环境信号。代谢酶如何介导葡萄糖信号仍然是一个谜。我们最近的研究结果表明，拟南芥HXK1介导葡萄糖信号而不具有代谢活性，并与两个HXK1非常规伙伴（HUP1：一种与HXK1， HUP2和转录因子（TFs）相互作用的支架蛋白）相互作用；HUP2：一种atp酶，与细胞核中的HXK1、HUP1和其他atp酶相互作用，控制转录和多种葡萄糖反应。本研究旨在阐明拟南芥核传感器HXK1控制葡萄糖信号转导的机制。本实验旨在利用分子、细胞、遗传和基因组方法阐明HXK1的功能和调控，并分析作用于核HXK1- hup1 /2复合物下游的两组信号调节因子。该项目将专注于利用转基因植物和葡萄糖传感器HXK1、HXK1信号伙伴HUP1、新型转录因子（MYB、SCL3、ZFP）和atp酶（HUP2/RPT5、RPT2和RPT6）中特定缺陷的功能缺失突变体，表征和整合8个拟南芥基因在葡萄糖信号传导中的功能。近全基因组微阵列和染色质免疫沉淀（ChIP）将用于鉴定HXK1的主要靶基因并表征其在体内的调控。该项目挑战了植物和动物基于代谢的葡萄糖反应的现有范式，旨在建立一个新的概念框架，以增强我们对植物向人类传递葡萄糖信号的分子和细胞机制的理解。三个具体目标是：阐明核葡萄糖传感器HXK1 Aim 2的功能和调控。表征hxk1 - hup1 /2介导的葡萄糖信号Aim 3中的三种新tf。定义核RPT5/2/6复合体中三个atp酶的功能。公共卫生相关性：尽管葡萄糖在基因表达、生理、代谢、细胞增殖和死亡、生长和发育以及人类疾病中发挥着核心作用，但在植物和动物中，葡萄糖信号的分子机制仍然是难以捉摸的。我们最近的研究提供了强有力的证据，证明葡萄糖信号可以从多细胞真核生物的葡萄糖代谢中解耦，并且拟南芥己糖激酶e1作为进化保守的传感器在核葡萄糖信号传导中起关键作用。该研究将发现新的调控因子并阐明其在核葡萄糖信号传导中的功能，为未来改善农业、环境和可再生能源生产，以及治疗糖尿病、肥胖、癌症和衰老等人类健康提供创新工具。

DESCRIPTION (provided by applicant): Glucose is an ancient and central signaling molecule in a broad range of organisms from E. coli, yeast to plants and humans. Despite the essential roles of glucose in gene expression, physiology, metabolism, cell proliferation and death, growth and development, and human diseases, the molecular and cellular mechanisms of glucose signaling remain mostly elusive in plants and animals. Our research in the model plant Arabidopsis thaliana has provided compelling genetic and biochemical evidence that hexokinase1 (HXK1) is an evolutionarily conserved glucose sensor that integrates nutrient and hormone signals to govern gene expression and plant growth in response to environmental cues. How the metabolic enzyme mediates glucose signaling remains a mystery. Our recent findings indicate that Arabidopsis HXK1 mediates glucose signaling without its metabolic activity, and interacts with two HXK1 Unconventional Partners (HUP1: a scaffolding protein interacting with HXK1, HUP2 and transcription factors (TFs); HUP2: an ATPase interacting with HXK1, HUP1 and other ATPases) in the nucleus to control transcription and diverse glucose responses. The goal of this research project is to elucidate the mechanisms of glucose signaling controlled by the nuclear sensor HXK1 in Arabidopsis. The proposed experiments aim to use molecular, cellular, genetic, and genomic approaches to elucidate HXK1 functions and regulation, and to analyze two sets of signaling regulators acting downstream of the nuclear HXK1-HUP1/2 complex. The project will focus on characterizing and integrating functions of eight Arabidopsis genes in glucose signaling using transgenic plants and loss-of-function mutants with specific defects in the glucose sensor HXK1, HXK1 signaling partners HUP1, novel transcription factors (MYB, SCL3, ZFP) and ATPases (HUP2/RPT5, RPT2 and RPT6). Near whole-genome microarray and chromatin-immunoprecipitation (ChIP) will be carried out to identify the primary HXK1 target genes and characterize their regulation in vivo. The project challenges the existing paradigm on metabolism-based glucose responses in plants and animals, and aims to build a new conceptual framework to enhance our understanding of the molecular and cellular mechanisms of glucose signaling from plants to humans. Three Specific Aims are: Aim 1. Elucidate the functions and regulation of the nuclear glucose sensor HXK1 Aim 2. Characterize three novel TFs in HXK1-HUP1/2-mediated glucose signaling Aim 3. Define functions of three ATPases in the nuclear RPT5/2/6 complex. PUBLIC HEALTH RELEVANCE: In spite the central roles of glucose in gene expression, physiology, metabolism, cell proliferation and death, growth and development, and human diseases, the molecular mechanisms of glucose signaling remain elusive in plants and animals. Our recent research has provided compelling evidence that glucose signaling can be uncoupled from glucose metabolism in multicellular eukaryotes, and Arabidopsis hexokinase1 acts as an evolutionarily conserved sensor playing a pivotal role in nuclear glucose signaling. The proposed research will discover novel regulators and elucidate their functions in nuclear glucose signaling, and provide innovative tools for future improvement of agriculture, environment and renewable energy production, as well as human health in treating diabetes, obesity, cancer and ageing modulated by glucose signaling.