Ribosomal Skipping Under Oxidative Stress in SLE

系统性红斑狼疮是一种慢性自身免疫综合征，可累及多种器官系统，常见于年轻人。 个人。已有研究表明，系统性红斑狼疮患者细胞中不受控制的氧化应激有助于 许多蛋白质、脂类和DNA的功能性氧化修饰，从而触发自身免疫。然而， RNA氧化在自身免疫性疾病的翻译和发展调节中起什么作用 系统性红斑狼疮尚不清楚。在正常和氧化应激条件下，rna的氧化水平都要高得多。 DNA氧化水平；然而，关于RNA氧化的潜在影响的现有信息很少。 尽管翻译调控的普遍性和重要性，我们对氧化作用的看法有限 压力会影响翻译和蛋白质多样化。关于RNA氧化的工作很少的一个主要原因是 认为正常的RNA周转应该减弱氧化的RNA对细胞新陈代谢和 基因表达。然而，由于RNA的氧化仅在几分钟内发生，而核糖体和非核糖体 编码RNA在细胞中持续数天，氧化的RNA有足够的机会具有有害和 长期的影响。我们的科学前提是MAVS寡聚诱导的5S RNA在 线粒体确保这种RNA被特定地氧化。我们认为氧化的5S RNA将促进 核糖体以跳过模式执行翻译，这将支持正常情况下蛋白质的翻译 在病毒感染的细胞压力下表达。我们建议，Aim1：在SLE患者中，表达较短的 不存在可抑制干扰素-I分泌的MAV的调节形式；AIM2：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：执行核糖体 对SLE T细胞的分析将使我们了解为什么氧化应激与MAV寡聚有关 限制天然免疫相关蛋白调节形式的翻译。

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.