Friday, November 22, 2024
11/22/2024
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.
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