The Nucleolar Detention Center: a Hub of Long Noncoding RNAs that Imprison Proteins During Stress

核仁拘留中心：在压力下囚禁蛋白质的长非编码 RNA 中心

• 批准号: 10355499
• 负责人: Stephen Lee
• 金额: $ 31.23万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-24 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10355499
• 关键词: Amyloid; Architecture; Biochemical Pathway; Biological; Biology; Cell Nucleolus; Cells; Cytoplasmic Structures; DNA; Data; Development; Dinucleoside Phosphates; Dinucleotide Repeats; Eukaryotic Cell; Exposure to; Family; Funding; Genome; Germ Cells; Grant; High temperature of physical object; Human Genome; Immobilization; Imprisonment; Investigation; Junk DNA; Laboratories; Length; Light; Liquid substance; Malignant Neoplasms; Membrane; Modeling; Molecular; Myocardial Infarction; National Institute of General Medical Sciences; Normal Cell; Nuclear; Nuclear Envelope; Organelles; Oxygen; Pathologic; Phase; Physiological; Physiological Processes; Play; Poly(A)+ RNA; Prisons; Process; Property; Protein Array; Protein Dynamics; Proteins; Publishing; RNA; RNA, Messenger, Stored; Radiation; Recovery; Regulatory Pathway; Repetitive Sequence; Reporting; Research; Ribosomes; Role; Scientist; Seeds; Solid; Stimulus; Stress; Stroke; System; Testing; Untranslated RNA; Work; amyloidogenesis; base; detention center; environmental stressor; experimental study; extreme temperature; granule cell; human disease; insight; interest; nervous system disorder; novel; programs; protein aminoacid sequence; recruit; response; stress granule; stressor

The Nucleolar Detention Center: A Hub of Long Noncoding RNA that Imprison Proteins During Stress NIGMS R01 (R01GM115342) Grant Renewal Project Summary The ability of cells to adapt to a wide variety of stress conditions plays a critical role in various physiological and pathological settings, including development, cancer and neurological disorders. In this current grant cycle, we reported the surprising discovery of stress-induced low complexity noncoding RNA derived from stimuli-specific loci of the ribosomal intergenic spacer (rIGSRNA); an enigmatic region of the human genome historically dismissed as “junk” DNA. We showed that low complexity rIGSRNA activate a physiological amyloidogenic program that converts the nucleolus into Amyloid Bodies (A-bodies): a molecular prison of immobilized proteins in an amyloid-like state. This rather unusual post-translational regulatory pathway enables cells to rapidly and reversibly store an array of endogenous proteins in A-bodies and enter quiescence in response to severe environmental insults. While many membrane-less compartments have been described as liquid-like (e.g. stress granules, P-bodies, germ cell granules), our discovery of A-bodies provided evidence of an amyloidogenic process that can physiologically transition biological matter to a solid-like state. In this grant renewal, we will show that the ribosomal intergenic spacer produces a large family of low complexity RNA that differ in their length, dinucleotide content and repetitive arrangement. These variable properties of rIGSRNA operate as architectural determinants that recruit common and distinct proteins to seed condition-specific A-bodies. We will also provide preliminary data that A-bodies enclose groups of polyadenylated RNA that may be involved in stress recovery. Conceptually, this NIGMS-funded research has uncovered an adaptive program that relies on a class of inducible low complexity RNA molecules to control cellular fate by assembling our newly-discovered nuclear membrane-less organelle: A-bodies. Based on these aforementioned rationales, we hypothesize that “Low complexity rIGSRNA activate physiological amyloidogenic programs that assemble stress-specific A-bodies”. In the Specific Aims, we will: 1. Uncover dinucleotide repeat motifs in rIGSRNA that seed A-bodies; 2. Explore the mechanisms that confer A-body identity; and 3. Examine processes involved in polyadenylated RNA storage by A-bodies. Our proposed work on low complexity rIGSRNA will open new lines of investigation on the physiological role of simple long intergenic dinucleotide repeats observed across the genome, but commonly ignored as non-functional DNA/RNA. In addition, the observation that low complexity RNA activate an amyloidogenic process of physiological liquid-to-solid transition will provide alternative insights into pathological amyloidogenesis involved in many human diseases. Finally, our planned experiments on polyadenylated RNA storage by A-bodies will unveil new regulatory pathways in RNA biology. Our research program is of general interest to scientists studying nuclear/cytoplasmic structures, cellular response to stress, long noncoding RNA biology, and physiological/pathological amyloidogenesis.

核仁滞留中心：在压力期间监禁蛋白质的长非编码RNA的枢纽 NIGMS R 01（R 01 GM 115342）赠款续期 项目摘要 细胞适应各种应激条件的能力在各种生理和病理过程中起着关键作用。 病理环境，包括发育、癌症和神经系统疾病。在当前的赠款周期中，我们 报道了一个令人惊讶的发现，应激诱导的低复杂性非编码RNA来源于刺激特异性 核糖体基因间间隔区（rIGSRNA）的基因座;历史上人类基因组的一个神秘区域 被认为是“垃圾”DNA我们发现，低复杂性的rIGSRNA激活了一种生理性淀粉样蛋白生成酶， 将核仁转化为淀粉样体（A体）的程序：固定蛋白质的分子监狱 处于淀粉样状态这种相当不寻常的翻译后调节途径使细胞能够快速和 可逆地将一系列内源性蛋白质储存在A体中，并响应于严重的 环境侮辱。虽然许多无膜隔室已被描述为液体样（例如，应力 颗粒，P-体，生殖细胞颗粒），我们发现的A-体提供了证据，淀粉样蛋白的形成。 生理学上可以将生物物质转变为固态的过程。在这次更新中，我们将 表明核糖体基因间间隔区产生了一个大家族的低复杂性RNA，它们在它们的 长度、二核苷酸含量和重复排列。rIGSRNA的这些可变特性起作用， 结构决定因素，招募共同和不同的蛋白质种子条件特异性A体。我们将 还提供了初步的数据，即A-体包围的多聚腺苷酸化的RNA组，可能涉及压力 复苏从概念上讲，这项由NIGMS资助的研究揭示了一个依赖于类的自适应程序， 可诱导的低复杂性RNA分子通过组装我们新发现的核 无膜细胞器：A体。基于上述理由，我们假设“低 复杂性rIGSRNA激活组装应激特异性A体的生理性淀粉样蛋白生成程序”。在 具体目标，我们将：1。发现在rIGSRNA中播种A体的二核苷酸重复基序; 2.探索 赋予A体身份的机制;以及3.通过以下方法检查多聚腺苷酸化RNA储存过程 A体。我们提出的低复杂性rIGSRNA的工作将开辟新的研究路线， 在整个基因组中观察到的简单长基因间二核苷酸重复的生理作用，但通常 作为非功能性DNA/RNA被忽略。此外，观察到低复杂性RNA激活了一个 生理性液体到固体转变的淀粉样蛋白生成过程将为病理性 淀粉样蛋白的生成与许多人类疾病有关。最后，我们计划的多聚腺苷酸化RNA实验 A体的储存将揭示RNA生物学中新的调控途径。我们的研究计划是一般的 感兴趣的科学家研究核/细胞质结构，细胞对压力的反应，长非编码RNA 生物学和生理/病理淀粉样蛋白生成。