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C6orf203 is an RNA-binding protein involved in mitochondrial protein synthesis

ABSTRACT: In all biological systems, RNAs are associated with RNA-binding proteins (RBPs), forming complexes that control gene regulatory mechanisms, from RNA synthesis to decay. In mammalian mitochondria, post-transcriptional regulation of gene expression is conducted by mitochondrial RBPs (mt-RBPs) at various stages of mt-RNA metabolism, including polycistronic transcript production, its processing into individual transcripts, mt-RNA modifications, stability, translation, and degradation. To date, only a handful of mt-RBPs have been characterized. Here, we describe a putative human mitochondrial protein, C6orf203, that contains an S4-like domain - an evolutionarily conserved RNA-binding domain previously identified in proteins involved in translation. Our data show C6orf203 to bind highly-structured RNA in vitro and associate with the mitoribosomal large subunit in HEK293T cells. Knockout of C6orf203 leads to a decrease in mitochondrial translation and consequent OXPHOS deficiency, without affecting mitochondrial RNA levels. Although mitoribosome stability is not affected in C6orf203-depleted cells, mitoribosome profiling analysis revealed a global disruption of the association of mt-mRNAs with the mitoribosome, suggesting that C6orf203 may be required for the proper maturation and functioning of the mitoribosome. We therefore propose C6orf203 to be a novel RNA-binding protein involved in mitochondrial translation, expanding the repertoire of factors engaged in this process.

ORGANISM(S): Homo sapiens

PROVIDER: GSE133315 | GEO | 2019/08/10

REPOSITORIES: GEO

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Project description:Mitochondrial ribosomes (mitoribosomes) have undergone substantial structural remodelling throughout evolution leading to distinct structural properties compared to their prokaryotic ancestors. Compared to their prokaryotic counterparts, mitoribosomes show a substantial loss of ribosomal RNA (rRNA), whilst acquiring unique mitochondrial proteins located on the periphery of the mitoribosome. This extended protein content suggests mitochondrial-specific functions of these proteins involved in mitochondrial mRNA selective-translation activation, ribosome assembly, translation regulation rather than exclusively structural scaffolding. We investigated the functional properties of the 14 unique (mitochondria-specific or supernumerary) mammalian mitoribosomal proteins (snMRP) in the small mitochondrial subunit (mtSSU) by CRISPR-mediated knockout and describe their specific effect on mitoribosome integrity and function. Unexpectedly, we show that each snMRP knockout leads to a unique pattern of mitoribosome instability with variable effects on mitochondrial protein synthesis as essential structural components and all – with the exception of mS37 (MRPS37, CHCHD1) – to almost complete loss of protein synthesis. Concomitantly, through steady-state proteomic analysis we confirm a modular assembly of the mtSSU. Surprisingly, mS37 was found to have impaired stability in all our tested mtSSU and large mitochondrial subunit (mtLSU) snMRPs knockouts as well as in patient-derived cell lines, suggesting an extended role of the protein in mtSSU pre-translation initiation steps. As mitochondrial intermembrane (IMS) targeted protein – a eukaryotic-confined localisation mechanism – with additional unique MIA40 (CHCHD4)-oxidisable motifs involved in the disulfide relay system, mS37 could have a specific role in mitochondrial translation regulation. Indeed, we find oxidation of the cysteines in the CX9C motif of mS37 to be essential for its stability, confirming mS37 regulating mitochondrial translation regulation.

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C6orf203 is an RNA-binding protein involved in mitochondrial protein synthesis

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