NSUN4 is a dual function mitochondrial protein required for both methylation of 12S rRNA and coordination of mitoribosomal assembly

PLoS Genet. 2014 Feb 6;10(2):e1004110. doi: 10.1371/journal.pgen.1004110. eCollection 2014 Feb.

Abstract

Biogenesis of mammalian mitochondrial ribosomes requires a concerted maturation of both the small (SSU) and large subunit (LSU). We demonstrate here that the m(5)C methyltransferase NSUN4, which forms a complex with MTERF4, is essential in mitochondrial ribosomal biogenesis as mitochondrial translation is abolished in conditional Nsun4 mouse knockouts. Deep sequencing of bisulfite-treated RNA shows that NSUN4 methylates cytosine 911 in 12S rRNA (m5C911) of the SSU. Surprisingly, NSUN4 does not need MTERF4 to generate this modification. Instead, the NSUN4/MTERF4 complex is required to assemble the SSU and LSU to form a monosome. NSUN4 is thus a dual function protein, which on the one hand is needed for 12S rRNA methylation and, on the other hand interacts with MTERF4 to facilitate monosome assembly. The presented data suggest that NSUN4 has a key role in controlling a final step in ribosome biogenesis to ensure that only the mature SSU and LSU are assembled.

MeSH terms

  • Animals
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • DNA Methylation / genetics
  • Methyltransferases / genetics*
  • Methyltransferases / metabolism
  • Mice
  • Mitochondria / genetics*
  • Mitochondria / metabolism
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Protein Binding
  • RNA, Ribosomal / biosynthesis
  • RNA, Ribosomal / genetics*
  • Ribosomes / genetics*
  • Ribosomes / ultrastructure
  • Transcription Factors / metabolism

Substances

  • Carrier Proteins
  • Mitochondrial Proteins
  • RNA, Ribosomal
  • RNA, ribosomal, 12S
  • Transcription Factors
  • mTERF protein, mouse
  • Methyltransferases
  • SHTAP protein, mouse

Grant support

This study was supported by an European Research Council Advanced Investigator grant to NGL and by the Deutsche Forschungsgemeinschaft, SFB 829 (NGL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.