PDF(Pubmed)
Abstract：
Mitochondria are essential regulators of innate immunity. They generate long mitochondrial double-stranded RNAs (mt-dsRNAs) and release them into the cytosol to trigger an immune response under pathological stress conditions. Yet the regulation of these self-immunogenic RNAs remains largely unknown. Here, we employ CRISPR screening on mitochondrial RNA (mtRNA)-binding proteins and identify NOP2/Sun RNA methyltransferase 4 (NSUN4) as a key regulator of mt-dsRNA expression in human cells. We find that NSUN4 induces 5-methylcytosine (m5C) modification on mtRNAs, especially on the termini of light-strand long noncoding RNAs. These m5C-modified RNAs are recognized by complement C1q-binding protein (C1QBP), which recruits polyribonucleotide nucleotidyltransferase to facilitate RNA turnover. Suppression of NSUN4 or C1QBP results in increased mt-dsRNA expression, while C1QBP deficiency also leads to increased cytosolic mt-dsRNAs and subsequent immune activation. Collectively, our study unveils the mechanism underlying the selective degradation of light-strand mtRNAs and establishes a molecular mark for mtRNA decay and cytosolic release.
摘要：
线粒体是先天免疫的重要调节因子。它们产生长的线粒体双链RNA(mt-dsRNA)并将它们释放到胞质溶胶中以在病理应激条件下触发免疫应答。然而，这些自身免疫原性RNA的调节在很大程度上仍然未知。这里,我们对线粒体RNA(mtRNA)结合蛋白进行CRISPR筛选,并确定NOP2/SunRNA甲基转移酶4(NSUN4)是人细胞中mt-dsRNA表达的关键调节因子.我们发现NSUN4在mtRNAs上诱导5-甲基胞嘧啶（m5C）修饰，特别是在轻链长链非编码RNA的末端。这些m5C修饰的RNA被补体C1q结合蛋白（C1QBP）识别，它募集多核糖核苷酸核苷酸转移酶来促进RNA周转。抑制NSUN4或C1QBP导致mt-dsRNA表达增加，而C1QBP缺乏也导致细胞溶质mt-dsRNA增加和随后的免疫激活。总的来说，我们的研究揭示了轻链mtRNAs选择性降解的潜在机制，并建立了mtRNA衰变和胞质释放的分子标记。
