Repression of ferritin light chain translation by human eIF3

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 5ʹ untranslated region (5ʹ-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 5ʹ-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.

In Vivo RNAi-Mediated eIF3m Knockdown Affects Ribosome Biogenesis and Transcription but Has Limited Impact on mRNA-Specific Translation

“…The LOC100862446 gene is an ortholog of Ftl1 , so it would also be detected as Ftl1 . Recently, it has been shown that eIF3 acts as a repressor of Ftl1 translation in vitro 33 . Our results confirm the link between eIF3 and Ftl1 and, for the first time, provide evidence for the repression of Ftl1 translation by eIF3 in vivo in the liver.…”

“…Interestingly, 4 out of the 6 identified genes are involved in the iron metabolism pathway (light- and heavy-chain ferritins LOC100862446 , Ftl1 , and Fth1 and hepcidin Hamp2 ). Recent research provides an additional confirmation for the link between eIF3 and ferritin genes 33 . Previously, photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) analysis showed interaction between ferritin light-chain (FTL) mRNA and eIF3 subunits 16 .…”

“…Previously, photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) analysis showed interaction between ferritin light-chain (FTL) mRNA and eIF3 subunits 16 . It has further been shown that eIF3 acts as a repressor of FTL mRNA translation and that eIF3-mediated Ftl repression is disrupted by a subset of SNPs in the FTL 5′ UTR that cause hyperferritinemia, a disease characterized by an overload of ferritin protein in the liver 33 , 58 . Our finding of eIF3m knockdown leading to increased Ftl1 translation efficiency is in agreement with these data; it also, for the first time, provides justification for the link between eIF3 and ferritins in vivo in the liver.…”

eIF-Three to Tango: emerging functions of translation initiation factor eIF3 in protein synthesis and disease

“…While eIF3 does not appear to bind to this element directly, removal of the motif strongly derepresses the translation of luciferase reporters in vitro and in vivo . Direct binding of eIF3 to a sequence motif in the 5′-UTR was recently implicated in translational suppression of the mRNA encoding ferritin light chain (FTL; Pulos-Holmes et al, 2019 ). The eIF3-binding motif contains two single nucleotide polymorphisms associated with hyperferritinemia.…”

Interactome Mapping of eIF3A in a Colon Cancer and an Immortalized Embryonic Cell Line Using Proximity-Dependent Biotin Identification

“…eIF3 plays a role in transcript-specific translation regulation [ 11 ], and eIF3 subunits bind directly to the HCV IRES element [ 12 , 13 , 14 ] and other secondary structures of mRNAs [ 15 ]. It is also involved in the repression of ferritin light chain translation [ 16 ]. Another binding partner of eIF3 is the RNA polymerase subunit hRPB11 [ 17 ].…”