GGNBP2 调控 ADAR1 编辑缺失后自身双链 RNA 引发的 MDA5 感应

GGNBP2 regulates MDA5 sensing triggered by self double-stranded RNA following loss of ADAR1 editing.

机构信息

St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia.

Department of Medicine, St. Vincent's Hospital, Melbourne Medical School, University of Melbourne, Fitzroy, VIC 3065, Australia.

出版信息

Sci Immunol. 2024 Nov 22;9(101):eadk0412. doi: 10.1126/sciimmunol.adk0412.

DOI:10.1126/sciimmunol.adk0412

PMID:39576872

Abstract

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 mutations and may be determinants of response or resistance to small-molecule ADAR1 inhibitors.

摘要

ADAR1 对双链 RNA（dsRNA）的腺苷到肌苷（A-to-I）编辑是细胞 dsRNA 免疫原性的重要调节剂。MDA5 在识别未经编辑的细胞 dsRNA 以及下游激活 I 型干扰素（IFN）信号转导中的作用已得到充分证实。然而，我们对修饰对未经编辑的 dsRNA 反应的途径的了解并不完整。我们进行了全基因组 CRISPR 筛选，并表明 GGNBP2、CNOT10 和 CNOT11 相互作用并调节对未经编辑的细胞 dsRNA 的感应。我们发现 GGNBP2 在 dsRNA 转录与其在 MDA5 细胞质中的感应之间起作用。GGNBP2 的缺失通过修饰内源性 A-to-I 编辑底物的亚细胞分布并减少细胞质 dsRNA 负荷，防止 ADAR1 编辑活性丧失后诱导 I 型 IFN 和自身炎症。这些发现揭示了修饰与突变相关疾病的先前未描述的途径，并且可能是对小分子 ADAR1 抑制剂的反应或耐药性的决定因素。