Abstract
A central problem in human biology remains the discovery of causal molecular links between mutations identified in genome-wide association studies (GWAS) and their corresponding disease traits. This challenge is magnified for variants residing in non-coding regions of the genome. Single-nucleotide polymorphisms (SNPs) in the 5' untranslated region (5'-UTR) of the ferritin light chain (FTL) gene that cause hyperferritinemia are reported to disrupt translation repression by altering iron regulatory protein (IRP) interactions with the FTL mRNA 5'-UTR. Here, we show that human eukaryotic translation initiation factor 3 (eIF3) acts as a distinct repressor of FTL mRNA translation, and eIF3-mediated FTL repression is disrupted by a subset of SNPs in FTL that cause hyperferritinemia. These results identify a direct role for eIF3-mediated translational control in a specific human disease.
Highlights
Iron is essential for a spectrum of metabolic pathways and cellular growth.if not properly managed, excess iron catalyzes the production of reactive oxygen species (ROS)
In order to understand the functional effect of the interaction between eukaryotic translation initiation factor 3 (eIF3) and ferritin light chain (FTL) mRNA, we utilized Renilla luciferase reporter mRNAs in which the 5ʹ untranslated region (5ʹ-UTR) from FTL was placed upstream of the Renilla coding sequence (Figure 1C)
These results suggest that eIF3 binding to the FTL 5ʹ-UTR represses FTL translation
Summary
If not properly managed, excess iron catalyzes the production of reactive oxygen species (ROS). To safeguard against these toxic effects, cells sequester iron in ferritin, a cage-like protein complex composed of a variable mixture of two structurally similar but functionally distinct subunits, the ferritin heavy chain (FTH) and the ferritin light chain (FTL) (Harrison and Arosio, 1996),(Knovich et al, 2009). The IRP-IRE interactions have been considered to be the sole posttranscriptional means of regulating ferritin expression, recent studies have provided strong evidence that other presently-unknown factors may provide another layer of regulation during FTL translation. We recently found that eIF3 can function beyond its scaffolding role in general
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