斯坦福大学Jin Billy Li小组在研究中取得进展。他们提出了只有一小部分细胞质dsRNAs需要ADAR1编辑来逃避MDA5介导的自身免疫。该研究于2025年12月3日发表于国际一流学术期刊《自然—遗传学》杂志上。

在这里，课题组研究人员发现人类免疫原性dsRNAs在所有细胞dsRNAs中只占很小的一部分。该课题组人员发现这些免疫原性dsRNAs在mRNAs中高度富集，并且内含子缺失，这与它们作为细胞质MDA5底物的作用一致。小组验证了这些dsRNAs的MDA5依赖性免疫原性，这些dsRNAs在ADAR1介导的RNA编辑后被抑制。值得注意的是，免疫原性dsRNAs在与常见炎症疾病相关的遗传易感性位点富集，这意味着它们的功能重要性。课题组研究人员预计，免疫原性dsRNA的焦点分析将增强对癌症和炎症性疾病的理解和治疗，在这些疾病中，dsRNA编辑和传感的作用越来越被认识到。

研究人员表示，未被RNA编辑酶ADAR1编辑的内源性长双链RNA （dsRNAs）可能激活抗病毒dsRNA受体MDA5，从而触发干扰素介导的免疫反应。在大量内源性长dsRNAs中，激活MDA5的关键底物（称为免疫原性dsRNAs）在很大程度上仍未确定。

附：英文原文

Title: ADAR1 editing is necessary for only a small subset of cytosolic dsRNAs to evade MDA5-mediated autoimmunity

Author: Sun, Tao, Li, Qin, Geisinger, Jonathan M., Hu, Shi-Bin, Fan, Boming, Su, Shichen, Tsui, Waitang, Guo, Hongchao, Ma, Jinbiao, Li, Jin Billy

Issue&Volume: 2025-12-03

Abstract: Endogenous long double-stranded RNAs (dsRNAs), which are not edited by the RNA editing enzyme ADAR1, may activate the antiviral dsRNA receptor MDA5 to trigger interferon-mediated immune responses. Among the large number of endogenous long dsRNAs, the key substrates that activate MDA5—termed as immunogenic dsRNAs—remain largely unidentified. Here we reveal that human immunogenic dsRNAs constitute a surprisingly small fraction of all cellular dsRNAs. We found that these immunogenic dsRNAs were highly enriched in mRNAs and depleted of introns, consistent with their role as cytosolic MDA5 substrates. We validated the MDA5-dependent immunogenicity of these dsRNAs, which was dampened following ADAR1-mediated RNA editing. Notably, immunogenic dsRNAs were enriched at genetic susceptibility loci associated with common inflammatory diseases, implying their functional importance. We anticipate that a focused analysis of immunogenic dsRNAs will enhance our understanding and treatment of cancer and inflammatory diseases, where the roles of dsRNA editing and sensing are increasingly recognized.

DOI: 10.1038/s41588-025-02430-9

Source: https://www.nature.com/articles/s41588-025-02430-9