Universität zu Köln

Metodiev, Metodi Dimitrov, Spahr, Henrik, Polosa, Paola Loguercio, Meharg, Caroline ORCID: 0000-0003-0573-9528, Becker, Christian, Altmueller, Janine, Habermann, Bianca ORCID: 0000-0002-2457-7504, Larsson, Nils-Goeran and Ruzzenente, Benedetta ORCID: 0000-0001-7366-114X (2014). NSUN4 Is a Dual Function Mitochondrial Protein Required for Both Methylation of 12S rRNA and Coordination of Mitoribosomal Assembly. PLoS Genet., 10 (2). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1553-7404

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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. Author Summary Mitochondria perform a number of essential functions in the cell, including synthesis of ATP via the oxidative phosphorylation (OXPHOS) system. Normal mitochondrial function requires coordinated expression of two genomes: mitochondria's own genome (mtDNA), which encodes 13 respiratory chain subunits with essential structural and functional roles for the OXPHOS system, and the nuclear genome encoding the remaining similar to 80 subunits. The mtDNA-encoded polypeptides are synthesized on mitochondrial ribosomes (mitoribosomes) located in the mitochondrial matrix. Biogenesis, maintenance and regulation of the complex mitochondrial translation apparatus are poorly understood despite its fundamental importance for cellular energy homeostasis. Here, we show that inactivation of the Nsun4 gene, encoding a mitochondrial m(5)C-methyltransferase, causes embryonic lethality, whereas tissue-specific disruption of Nsun4 in the heart causes cardiomyopathy with mitochondrial dysfunction. By performing sequencing of bisulfite-treated RNA we report that NSUN4 methylates C911 in 12S rRNA of the small ribosomal subunit. Surprisingly, NSUN4 can on its own perform this rRNA modification, whereas interaction with its partner protein MTERF4 is required for assembly of functional ribosomes. NSUN4 thus has dual roles in ribosome maturation and performs an important final quality control step to ensure that only mature mitoribosomal subunits are assembled into functional ribosomes.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Metodiev, Metodi Dimitrov UNSPECIFIED UNSPECIFIED UNSPECIFIED Spahr, Henrik UNSPECIFIED UNSPECIFIED UNSPECIFIED Polosa, Paola Loguercio UNSPECIFIED UNSPECIFIED UNSPECIFIED Meharg, Caroline UNSPECIFIED orcid.org/0000-0003-0573-9528 UNSPECIFIED Becker, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Habermann, Bianca UNSPECIFIED orcid.org/0000-0002-2457-7504 UNSPECIFIED Larsson, Nils-Goeran UNSPECIFIED UNSPECIFIED UNSPECIFIED Ruzzenente, Benedetta UNSPECIFIED orcid.org/0000-0001-7366-114X UNSPECIFIED
URN:	urn:nbn:de:hbz:38-447874
DOI:	10.1371/journal.pgen.1004110
Journal or Publication Title:	PLoS Genet.
Volume:	10
Number:	2
Date:	2014
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1553-7404
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MTDNA TRANSCRIPTION; TERMINATION FACTOR; DIMETHYLASE DIM1P; METHYLTRANSFERASE; COMPLEX; YEAST; IDENTIFICATION; TRANSLATION; BIOGENESIS; STABILITY Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/44787