The nonsense-mediated mRNA decay (NMD) pathway differentially regulates COX17, COX19 and COX23 mRNAs

Abstract

The differential regulation of COX17, COX19 and COX23 mRNAs by the nonsense-mediated mRNA decay (NMD) pathway was investigated. The NMD pathway regulates mRNAs that aberrantly terminate translation. This includes mRNAs harboring premature translation termination codons and natural mRNAs. Most natural mRNAs regulated by NMD encode fully functional proteins involved in various cellular processes. However, the cause and targeting of most of these mRNAs by the pathway is not understood. Analysis of a set of mRNAs involved in copper homeostasis showed that a subset of these mRNAs function in mitochondrial copper homeostasis. Here, we examined the regulation of COX17, COX19 and COX23 mRNAs by NMD. These mRNAs encode homologous mitochondrial proteins involved in metallation of cytochrome c oxidase. We found that COX17, COX19 and COX23 mRNAs are differentially regulated by NMD depending on environmental copper levels. A long 3′-UTR contributes to the direct regulation of COX19 mRNA by the pathway. Alternatively, COX23 mRNA contains a long 3′-UTR, but is indirectly regulated by the pathway under two conditions tested here. Analysis of the functionality of the NMD targeting features in COX23 mRNA showed that the COX23 3′-UTR is sufficient to trigger NMD. The regulation of mRNAs involved in mitochondrial copper metabolism by NMD is physiologically significant because excess copper enhances growth of NMD mutants on a non-fermentable carbon source. These findings suggest that regulation of mRNAs encoding homologous proteins by NMD can be differential depending on environmental copper levels. Furthermore, these findings suggest copper ion homeostatic mechanisms in the mitochondria occur at the mRNA level via the NMD pathway.

Variation of the response to metal ions and nonsense‐mediated mRNA decay across different Saccharomyces cerevisiae genetic backgrounds

“…These NMD regulated transcripts include mRNAs that encode proteins involved in copper transport, mitochondrial copper homeostasis (Murtha et al, 2018), and protection from metal toxicity. The two mRNAs found to be regulated by NMD and involved in protection from metal toxicity are CRS5 and PCA1 (M. Peccarelli et al, 2016).…”

“…The major metallothionein, CUP1 , is induced by the ACE1 transcription factor when yeast cells are exposed to elevated copper levels (Wang et al, 2013). Interestingly, CUP1 mRNA is not regulated by NMD, whereas CRS5 is an indirect NMD target (Murtha et al, 2018; M. Peccarelli et al, 2016). The decay rate of the CRS5 mRNA is comparable in wild‐type and NMD mutant yeast cells grown in rich media.…”

A 17-bp InDel (rs668420586) within goat CHCHD7 gene located in growth-related QTL affecting body measurement traits

“…The products encoded by CHCHD7 are essential conserved factors for the assembly of cytochrome C oxidase present in the mitochondrial membrane space (Barros et al 2004;Cavallaro 2010;Banci et al 2012). Cytochrome C oxidase, an enzyme at the end of the mitochondrial electron transport chain, is a typical copper-containing enzyme involved in bone cell metabolism, indicating that CHCHD7 is indirectly involved in the growth and development of animals (Liu 2017;Murtha et al 2019). Moreover, CHCHD7 protein is potentially involved in copper (Cu) delivery during cytochrome C oxidase (CcO) biosynthesis, Cu homeostasis, or the Cox1 heme during heme transfer (Dela Cruz et al 2016;Murtha et al 2019).…”

Nonsense‐mediated mRNA decay of the ferric and cupric reductase mRNAs FRE1 and FRE2 in Saccharomyces cerevisiae

“…Nevertheless, it is important to note that the presence of any NMD‐targeting feature on an mRNA does not always elicit NMD . These observations suggest that NMD targeting can function in specific cellular context and environmental conditions .…”