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Ribosomal Skipping Under Oxidative Stress in SLE

SLE 中氧化应激下的核糖体跳跃

基本信息

批准号：
9933193
负责人：
Iwona Agnieszka Koenig
金额：
$ 35.28万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9933193
关键词：
Affect Agreement Amino Acids Antioxidants Antiviral Agents Autoantibodies Autoimmune Diseases Autoimmune Process Autoimmunity B-Lymphocytes CD19 gene CD3 Antigens Cell Line Cells Cellular Metabolic Process Cellular Stress Chronic Cysteine DNA Data Dendritic Cells Detection Development Disease Disulfides Ensure Environmental Exposure Exposure to Functional disorder Gene Expression Genetic Translation Homeostasis Immune Individual Initiator Codon Interferon Type I Interferons Length Lipids Lymphoid Cell Messenger RNA Metabolic Metabolic dysfunction Mitochondria Mitochondrial Matrix Modeling Modification Mus Mutation N-terminal Natural Immunity Open Reading Frames Oxidants Oxidative Stress Oxides Paraquat Pathologic Pathway interactions Patients Peripheral Blood Mononuclear Cell Play Prevalence Prevalence Study Process Production Proteins Proteome Publishing RNA RNA Splicing Reactive Oxygen Species Regulation Ribosomes Role Serum Signal Transduction Signaling Protein Stress Syndrome Systemic Lupus Erythematosus T-Lymphocyte Testing Translation Initiation Translational Regulation Translations Untranslated RNA Variant Virus Diseases Work base body system disulfide bond indexing mitochondrial dysfunction mitochondrial metabolism monomer myxothiazol novel oxidation pathogen prevent response ribosome profiling

项目摘要

SLE is a chronic autoimmune syndrome that can involve a variety of organ systems and frequently affects young individuals. It has been suggested that uncontrolled oxidative stress in the cells of SLE patients contributes to functional oxidative modifications of many proteins, lipids, and DNA, thereby triggering autoimmunity. However, what role RNA oxidation plays in the regulation of translation and development of autoimmune diseases such as SLE is not known. Under both normal and oxidative stress conditions, RNA oxidation levels are much higher than DNA oxidation levels; however, available information on the potential effects of RNA oxidation is scarce and despite the prevalence and importance of translational regulation, we have a limited view of how oxidative stress affects translation and protein diversification. A major reason for the paucity of work on RNA oxidation is the misconception that normal RNA turnover should diminish the effects of oxidized RNA on cell metabolism and gene expression. However, because oxidation of RNA occurs in just a few minutes, and ribosomal and non- coding RNAs persist in the cell for days, there is ample opportunity for oxidized RNA to have deleterious and long-standing effects. Our scientific premise is that MAVS oligomerization-induced accumulation of 5S RNA at the mitochondria ensures that this RNA is specifically oxidized. We propose that oxidized 5S RNA will promote ribosomes to perform translation in a skipping mode, which will support translation of proteins that are normally expressed under cellular stress of viral infection. We propose that, Aim1: In SLE patients, expression of a shorter regulatory form of MAVS, which can suppress IFN-I secretion, is not present; Aim2: non-coding ribosomal RNA, like 5S RNA in SLE patients, is oxidized and promotes ribosomal skipping; and Aim 3: performing ribosomal profiling of SLE T cells will allow us to understand why oxidative stress associated with MAVS oligomerization limits the translation of regulatory forms of innate immunity associated proteins.

SLE 是一种慢性自身免疫综合征，可累及多种器官系统，经常影响年轻人个人。有人提出，系统性红斑狼疮患者细胞中不受控制的氧化应激会导致许多蛋白质、脂质和 DNA 的功能性氧化修饰，从而引发自身免疫。然而， RNA氧化在翻译调节和自身免疫性疾病（例如， SLE 尚不清楚。在正常和氧化应激条件下，RNA 氧化水平要高得多高于 DNA 氧化水平；然而，关于 RNA 氧化潜在影响的可用信息很少尽管翻译调控很普遍且很重要，但我们对氧化如何发挥作用的认识有限。压力影响翻译和蛋白质多样化。 RNA 氧化工作缺乏的一个主要原因是认为正常 RNA 周转会减少氧化 RNA 对细胞代谢的影响的误解基因表达。然而，由于RNA的氧化发生在短短几分钟内，并且核糖体和非- 由于编码 RNA 在细胞中持续存在数天，因此氧化的 RNA 有足够的机会产生有害的和长期影响。我们的科学前提是 MAVS 寡聚化诱导 5S RNA 的积累线粒体确保该 RNA 被特异性氧化。我们认为氧化的 5S RNA 将促进核糖体以跳跃模式进行翻译，这将支持通常情况下蛋白质的翻译在病毒感染的细胞应激下表达。我们建议，目标 1：在 SLE 患者中，表达较短的不存在可以抑制 IFN-I 分泌的 MAVS 的调节形式；目标2：非编码核糖体RNA，与 SLE 患者中的 5S RNA 一样，被氧化并促进核糖体跳跃；目标 3：进行核糖体 SLE T 细胞的分析将使我们能够了解为什么氧化应激与 MAVS 寡聚化相关限制先天免疫相关蛋白的调节形式的翻译。