Understanding the epitranscriptional rules of escaping detrimental innate immune activation

了解逃避有害先天免疫激活的表观转录规则

• 批准号: 2601373
• 金额: --
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2601373
• 关键词: Understanding; epitranscriptional; rules; escaping; detrimental

Our cells have evolved special sensors (RLR-signalling) to rapidly mount a protective, immunological response to the presence of long, perfectly paired double-stranded RNAs (dsRNAs), indicative of viral invasion. Intriguingly, our cells have the "blueprints" for generating such dsRNAs (e.g Alu-repeats for humans and SINEs/LINEs-repeats for mice), but these apparently escape cytoplasmic sensing. Studies suggest that adenosine deaminase acting on RNA-1 (ADAR1) grants immunosuppressive properties to our dsRNAs by converting adenosines to inosines (i.e A-to-I RNA-editing) (Science.2015;349(6252):1115-20). Despite the requirement of ADAR1-mediated epitranscriptomic changes for life, it remains a mystery how exactly these suppress the endogenous dsRNA-sensing. We demonstrated that ADAR1 is highly expressed in vascular endothelial cells(ECs) and edits Alu-dsRNAs, unwinding them into more linear structures (Nat Med.2016;22(10):1140-1150) due to unstable I:U pairs. ECs line the interior of blood vessels thus contributing to innate immunity in all organs and diseases. Our previous work has linked vascular ADAR1-induced Alu-dsRNA-editing to inflammatory and autoimmune diseases (Nat Med.2016;22(10):1140-1150; J Autoimmun.2020;106:102329). We hypothesize that EC RNA-editing is particularly important for innate immunity and functions through impeding the deleterious accumulation of immunostimulatory-dsRNAs.

我们的细胞已经进化出了特殊的传感器（rlr信号），可以对指示病毒入侵的长而完美配对的双链rna （dsRNAs）的存在迅速产生保护性免疫反应。有趣的是，我们的细胞有生成这些dsrna的“蓝图”（例如人类的alu -repeat和小鼠的sin / lines -repeat），但这些显然逃脱了细胞质的感知。研究表明，作用于RNA-1的腺苷脱氨酶（ADAR1）通过将腺苷转化为肌苷（即A-to-I rna编辑）赋予我们的dsRNAs免疫抑制特性（Science.2015;349(6252):1115-20）。尽管生命需要adar1介导的表转录组变化，但这些变化究竟如何抑制内源性dsrna感知仍然是一个谜。我们证明，由于I:U对不稳定，ADAR1在血管内皮细胞（ECs）中高度表达，并编辑Alu-dsRNAs，将其解绕成更线性的结构（Nat Med.2016;22(10):1140-1150）。内皮细胞排列在血管内部，因此有助于所有器官和疾病的先天免疫。我们之前的工作已经将血管adar1诱导的alu - dsrna编辑与炎症和自身免疫性疾病联系起来(Nat Med.2016;22(10):1140-1150；J Autoimmun.2020; 106:102329)。我们假设EC rna编辑对先天免疫和功能特别重要，通过阻碍免疫刺激- dsrna的有害积累。