Abstract
Selenoproteins are a group of selenocysteine-containing proteins with major roles in cellular antioxidant defense and thyroid hormone metabolism. Selenoprotein expression is determined by hierarchical mechanisms that result in tissue-specific levels. Current data inadequately explain the abundance of various selenoproteins under normal and pathological conditions, including in pancreatic β-cells. Selenocysteine insertion sequence binding protein 2 (SBP2) is a critical protein in selenoprotein translation that also plays an essential role in stabilizing selenoprotein transcripts by antagonizing nonsense-mediated decay (NMD). Importantly, dysfunctional SBP2 is associated with endocrine disorders in humans. Here we describe the impact of induced Sbp2 deficiency in pancreatic β-cells on selenoprotein transcript profiles in the pancreatic islets of C57BL/6J mice. Sex differences were noted in control mice, in which female islets showed 5 selenoproteins decreased and one increased versus male islets. Induced Sbp2 deficiency in pancreatic β-cells altered expression of only 3 selenoprotein transcripts in male islets, whereas 14 transcripts were reduced in female islets. In all cases, decreased transcription was observed in genes known to be regulated by NMD. The differential impact of Sbp2 deletion on selenoprotein transcription between sexes suggests sex-specific hierarchical mechanisms of selenoprotein expression that may influence islet biology and consequentially metabolic disease risk.
Highlights
The pancreatic islets of Langerhans proteome plays a central role in the homeostatic regulation of glucose metabolism
Exon 14 was targeted for deletion as it encodes part of the C terminus functional domains that are highly conserved across species and required for Sec-insertion sequence (SECIS) binding, ribosome binding, and Sec incorporation
We found that mRNA expression of Selenom, Selenow, Gpx[1], Gpx[4], and Selenon were decreased while Selenoi, a non-nonsense-mediated decay (NMD)-susceptible selenoprotein was significantly increased in the female control mouse (Sbp[2] fl/fl) islets compared to their male counterparts (Fig. 2)
Summary
The pancreatic islets of Langerhans proteome plays a central role in the homeostatic regulation of glucose metabolism. An in-frame UGA stop codon in the selenoprotein mRNA is recoded as the selenium-containing amino acid Sec, which is incorporated into the protein structure by a complex multicomponent machinery Key to this process are the Sec-insertion sequence (SECIS) element in the 3′-untranslated region (UTR), a Sec-specific elongation factor (EFsec), and the SECIS-binding protein-2 (SBP2)[2,5,6,7]. In addition to its role in selenoprotein translation, SBP2 is essential for the upstream stabilization of selenoprotein mRNA Because of their essential roles in regulating cellular oxidative homeostasis, it is likely that disruptions in selenoprotein synthesis will lead to cellular dysfunction and consequential adverse health effects. Mouse models conditionally deficient in Sbp[2] gene expression have been proposed as models to study the tissuespecific function of individual selenoproteins[19], here we present the selenoprotein gene expression profiles in pancreatic islets from mice we developed that have an inducible β-cell-specific Sbp[2] gene deletion and discuss the sex-specific differential gene expression of selenoproteins in murine islets
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