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， 个体已经表明，SLE患者细胞中不受控制的氧化应激有助于 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，在这方面， RNA氧化在自身免疫性疾病的翻译和发展中起着什么作用， SLE未知。在正常和氧化应激条件下， 然而，关于RNA氧化的潜在影响的可用信息很少 尽管翻译调节的普遍性和重要性，我们对氧化调节是如何发生的看法有限。 应激影响翻译和蛋白质多样化。关于RNA氧化的研究很少的主要原因是 错误的观念认为正常的RNA周转应该减少氧化的RNA对细胞代谢的影响， 基因表达。然而，由于RNA的氧化发生在短短几分钟内，而核糖体和非核糖体的氧化则发生在几分钟内。 当编码RNA在细胞中持续存在数天时，氧化的RNA有足够的机会具有有害的， 长期影响。我们的科学前提是，MAVS寡聚化诱导的5S RNA的积累， 线粒体确保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，这将支持正常情况下 在病毒感染的细胞应激下表达。我们认为，Aim 1：在SLE患者中， 不存在可抑制IFN-1分泌的MAVS的调节形式; Aim2：非编码核糖体RNA， 像SLE患者中的5S RNA一样，被氧化并促进核糖体跳跃;目标3：进行核糖体跳跃 分析SLE T细胞将使我们了解为什么氧化应激与MAVS寡聚化相关 限制了先天免疫相关蛋白的调节形式的翻译。

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.