Adenosine-to-inosine (A-to-I) editing of double-stranded RNA (dsRNA) by ADAR1 is an essential modifier of the immunogenicity of cellular dsRNA. The role of MDA5 in sensing unedited cellular dsRNA and the downstream activation of type I interferon (IFN) signaling are well established. However, we have an incomplete understanding of pathways that modify the response to unedited dsRNA. We performed a genome-wide CRISPR screen and showed that GGNBP2, CNOT10, and CNOT11 interact and regulate sensing of unedited cellular dsRNA. We found that GGNBP2 acts between dsRNA transcription and its cytoplasmic sensing by MDA5. GGNBP2 loss prevented induction of type I IFN and autoinflammation after the loss of ADAR1 editing activity by modifying the subcellular distribution of endogenous A-to-I editing substrates and reducing cytoplasmic dsRNA load. These findings reveal previously undescribed pathways to modify diseases associated with ADAR mutations and may be determinants of response or resistance to small-molecule ADAR1 inhibitors.

中文翻译：

---

GGNBP2 调节 ADAR1 编辑丢失后由自双链 RNA 触发的 MDA5 感应


ADAR1 对双链 RNA （dsRNA） 的腺苷-肌苷 （A-to-I） 编辑是细胞 dsRNA 免疫原性的重要修饰剂。MDA5 在感应未编辑的细胞 dsRNA 和 I 型干扰素 （IFN） 信号转导的下游激活中的作用已得到充分证实。然而，我们对改变对未编辑 dsRNA 的反应的途径了解不完全。我们进行了全基因组 CRISPR 筛选，结果表明 GGNBP2 、 CNOT10 和 CNOT11 相互作用并调节未编辑细胞 dsRNA 的感应。我们发现 GGNBP2 在 dsRNA 转录和 MDA5 的细胞质感应之间发挥作用。GGNBP2 缺失通过改变内源性 A-to-I 编辑底物的亚细胞分布和减少细胞质 dsRNA 载量，阻止了 I 型 IFN 的诱导和 ADAR1 编辑活性丧失后的自身炎症。这些发现揭示了以前未描述的改变与 ADAR 突变相关的疾病的途径，并且可能是对小分子 ADAR1 抑制剂反应或耐药的决定因素。