eIF6 coordinates insulin sensitivity and lipid metabolism by coupling translation to transcription

Abstract

Insulin regulates glycaemia, lipogenesis and increases mRNA translation. Cells with reduced eukaryotic initiation factor 6 (eIF6) do not increase translation in response to insulin. The role of insulin-regulated translation is unknown. Here we show that reduction of insulin-regulated translation in mice heterozygous for eIF6 results in normal glycaemia, but less blood cholesterol and triglycerides. eIF6 controls fatty acid synthesis and glycolysis in a cell autonomous fashion. eIF6 acts by exerting translational control of adipogenic transcription factors like C/EBPβ, C/EBPδ and ATF4 that have G/C rich or uORF sequences in their 5′ UTR. The outcome of the translational activation by eIF6 is a reshaping of gene expression with increased levels of lipogenic and glycolytic enzymes. Finally, eIF6 levels modulate histone acetylation and amounts of rate-limiting fatty acid synthase (Fasn) mRNA. Since obesity, type 2 diabetes, and cancer require a Fasn-driven lipogenic state, we propose that eIF6 could be a therapeutic target for these diseases.

SBDS-Deficient Cells Have an Altered Homeostatic Equilibrium due to Translational Inefficiency Which Explains their Reduced Fitness and Provides a Logical Framework for Intervention

“…Other snoRNAs were not changed (Fig 4F; S1 and S2 Files). Intriguingly, there was no overlap between the genes regulated at the polysomal level by Sbds mutation (S1 File), to the ones we previously found regulated by eIF6 deficiency [41]. …”

“…We focused our attention on information deriving from LINCS/CMap project to evaluate if the gene expression profile found altered in the total fraction of Sbds R126T/R126T MEFs cells was similar to transcriptional changes induced by drugs, observed in other cell types and to eIF6 deficiency [41]. Analysis performed by Query web tool on the complete list of modulated genes, and on a subset of the most changed ones identifies three common PKC activators: ingenol, phorbol-12-myristate-13-acetate and prostratin (S3 File).…”

“…Similarly to SBDS mutants, eIF6 depletion protects from oncogene-induced transformation [25, 47], whereas its amplification is oncogenic [48, 49]. eIF6 depletion does not induce senescence [25], but induces a different transcriptional rewiring [41], a divergent bone marrow phenotype affecting platelets [50], and a generally improved metabolic status [41]. SBDS depletion reduces the translation of mRNAs undergoing reinitiation, as CEBP/β derived LIP peptide [26].…”

Suboptimal T-cell receptor signaling compromises protein translation, ribosome biogenesis, and proliferation of mouse CD8 T cells

“…For example, differences in the abundance of proteins, such as eIF6, between WT and Lck −/− T cells may have influenced the range of mRNA species that are translated. The antiassociation factor eIF6 prevents premature binding of 40S and 60S ribosome subunits (38) and has been shown to affect G1/S cell cycle transition (39,40) and the expression of metabolic enzymes controlling fatty acid synthesis and glycolysis (41). A G1/S block was observed in Lck −/− cells at 24 h after stimulation, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that fatty acid metabolism was highly enriched in the translationally repressed gene subset in Lck −/− cells.…”

“…Depletion of Tif6 in yeast results in loss of 60S ribosome, which can be rescued by ectopic expression of human eIF6 (42)(43)(44), suggesting a possible role of eIF6 in ribosome biogenesis in mammalian cells. eIF6 is also known to regulate translation of a subset of mRNAs containing upstream (u)ORF motifs in their 5′ UTR (41). Overexpression of eIF6 in a murine mast cell line enhanced the production of IL-2 (45), which contains uORF in its transcript (46).…”