{Reference Type}: Journal Article
{Title}: RNA 5-methylcytosine marks mitochondrial double-stranded RNAs for degradation and cytosolic release.
{Author}: Kim S;Tan S;Ku J;Widowati TA;Ku D;Lee K;You K;Kim Y;
{Journal}: Mol Cell
{Volume}: 84
{Issue}: 15
{Year}: 2024 Aug 8
{Factor}: 19.328
{DOI}: 10.1016/j.molcel.2024.06.023
{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.