Intracellular trafficking of micronutrients: from gene regulation to nutrient requirements

Abstract

Professor John Hesketh, fax +44 191 222 8684, email J.E. Hesketh@ncl.ac.uk The intracellular distribution of micronutrients, as well as their uptake, is important for cell function. In some cases the distribution of micronutrients or their related proteins is determined by gene expression mechanisms. The 3′ untranslated region (3′UTR) of metallothionein-1 mRNA determines localisation of the mRNA, and in turn intracellular trafficking of the protein product. Using transfected cells we have evidence for the trafficking of metallothionein-1 into the nucleus and for its involvement in protection from oxidative stress and DNA damage. When nutritional supply of Se is limited, selenoprotein expression is altered, but not all selenoproteins are affected equally; the available Se is prioritised for synthesis of particular selenoproteins. The prioritisation involves differences in mRNA translation and stability due to 3′UTR sequences. Potentially, genetic variation in these regulatory mechanisms may affect nutrient requirements. Genetic polymorphisms in the 3′UTR from two selenoprotein genes have been observed; one polymorphism affects selenoprotein synthesis. These examples illustrate how molecular approaches can contribute at several levels to an increased understanding of nutrient metabolism and requirements. First, they provide the tools to investigate regulatory features in genes and their products. Second, understanding these processes can provide model systems to investigate nutrient metabolism at the cellular level. Third, once key features have been identified, the availability of human genome sequence information and single nucleotide polymorphism databases present possibilities to define the extent of genetic variation in genes of nutritional relevance. Ultimately, the functionality of any variations can be defined and subgroups of the population with subtly different nutrient requirements identified. RésuméLa distribution intracellulaire des micronutriments ainsi que leur absorption sont importantes pour les fonctions cellulaires. Dans certains cas la distribution des micronutriments ou des protéines associées est déterminée par des mécanismes liés à l'expression des gènes. La région 3′ non traduite (3′UTR) de l'ARNm de la métallothioneine-1 détermine la localisation de ce message et, par conséquent, la localisation intracellulaire de la protéine qu'il code. En utilisant des cellules transfectées nous avons montré que la métallothioneine-1 est transportée vers le noyau ou elle exerce un rôle dans la protection contre le stress oxydant et les dommages causés à l'ADN. Quand l'apport nutritionnel en Se est limité, l'expression des sélénoproteines est altérée. Toutefois celleci n'est pas affectée de façon identique pour toutes les sélénoproteines; le Se disponible étant utilisé de façon prioritaire pour la synthèse de certaines d'entre elles. Cet ordre de priorité met en jeu des différences dans la traduction et la stabilité de leur ARNm qui sont sous le contrôle de séquences dans la région 3′ non traduite. Pot...

Relevance of selenoprotein transcripts for selenium status in humans

“…Se supplementation is known to modulate the relative ratio between these two isoforms and promote the methylation of Sec tRNA[Ser]Sec. (Hatfield and Gladyshev 2002; Hesketh and Villette 2002; Jameson and Diamond 2004; Schomburg and Schweizer 2009; Small-Howard and Berry 2005). …”

3′-Untranslated regions are important in mRNA localization and translation: lessons from selenium and metallothionein

“…UGA was originally identified as a stop codon so its use as a codon for selenocysteine requires a recoding and this process uses additional signals within the mRNA itself. In mammalian cells, this recoding involves a specific RNA stem-loop structure SECIS (selenocysteine insertion sequence) in the 3 -UTR of selenoprotein mRNAs and a series of specific protein factors, including SBP2 (SECIS-binding protein 2) [2,[15][16][17].…”

“…how nutrients affect promoter activity and transcription factors. However, the increasing evidence that post-transcriptional mechanisms are critical in gene regulation leads to the conclusion that the study of nutrient-gene interactions must involve consideration of RNA-based gene regulation involving the 5 -and 3 -UTRs (untranslated regions) [1,2].…”

Nutrigenetics, Nutrigenomics, and Selenium

“…We are now able, at a relatively low cost, to estimate selenoprotein genotype in relation to uptake and metabolism (Joost et al, 2007; Méplan et al, 2007; Williams et al, 2008; Rayman, 2009). Additionally, we are able to understand the consequences of human health status and genetic variation for expression of key Se-related genes (Hesketh and Villette, 2002; Hesketh et al, 2006; Hesketh, 2008). The new molecular technologies pave the way for personalized nutrition and optimal status of micronutrients such as Se.…”