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RNA 5-methylcytosine marks mitochondrial double-stranded RNAs for degradation and cytosolic release.
- Source :
-
Molecular Cell . Aug2024, Vol. 84 Issue 15, p2935-2935. 1p. - Publication Year :
- 2024
-
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. [Display omitted] • CRISPR screening of mt-RBPs reveals key regulators of mt-dsRNA expression • NSUN4 installs m5C RNA modification on mitochondrial mRNAs and lncRNAs • C1QBP recognizes m5C-modified mitochondrial RNAs and recruits PNPT1 • m5C modification marks the mitochondrial RNAs for decay and cytosolic release Through CRISPR screening of 89 mitochondrial RBPs, Kim et al. find that NSUN4 downregulates mitochondrial dsRNA expression by installing 5-methylcytosine modification on light-strand RNAs. The modified RNAs are recognized by C1QBP, which recruits PNPT1 to facilitate RNA turnover, and are released to the cytosol, where they activate the immune response. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 10972765
- Volume :
- 84
- Issue :
- 15
- Database :
- Academic Search Index
- Journal :
- Molecular Cell
- Publication Type :
- Academic Journal
- Accession number :
- 178857821
- Full Text :
- https://doi.org/10.1016/j.molcel.2024.06.023