Eukaryotic translation initiation factor 6 is a novel regulator of reactive oxygen species‐dependent megakaryocyte maturation

Ricciardi, Sara; Miluzio, Annarita; Brina, Daniela; Clarke, Kim; Bonomo, Michela; Aiolfi, Roberto; Guidotti, Luca G.; Falciani, Francesco; Biffo, Stefano

doi:10.1111/jth.13150

Cited by 13 publications

(12 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

View full text Add to dashboard Cite

Ribosomopathies are a family of inherited disorders caused by mutations in genes necessary for ribosomal function. Shwachman-Diamond Bodian Syndrome (SDS) is an autosomal recessive disease caused, in most patients, by mutations of the SBDS gene. SBDS is a protein required for the maturation of 60S ribosomes. SDS patients present exocrine pancreatic insufficiency, neutropenia, chronic infections, and skeletal abnormalities. Later in life, patients are prone to myelodisplastic syndrome and acute myeloid leukemia (AML). It is unknown why patients develop AML and which cellular alterations are directly due to the loss of the SBDS protein. Here we derived mouse embryonic fibroblast lines from an SbdsR126T/R126T mouse model. After their immortalization, we reconstituted them by adding wild type Sbds. We then performed a comprehensive analysis of cellular functions including colony formation, translational and transcriptional RNA-seq, stress and drug sensitivity. We show that: 1. Mutant Sbds causes a reduction in cellular clonogenic capability and oncogene-induced transformation. 2. Mutant Sbds causes a marked increase in immature 60S subunits, limited impact on mRNA specific initiation of translation, but reduced global protein synthesis capability. 3. Chronic loss of SBDS activity leads to a rewiring of gene expression with reduced ribosomal capability, but increased lysosomal and catabolic activity. 4. Consistently with the gene signature, we found that SBDS loss causes a reduction in ATP and lactate levels, and increased susceptibility to DNA damage. Combining our data, we conclude that a cell-specific fragile phenotype occurs when SBDS protein drops below a threshold level, and propose a new interpretation of the disease.

show abstract

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

View full text Add to dashboard Cite

show abstract

“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Tan

Knight

Sbarrato

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Global transcriptomic and proteomic analyses of T cells have been rich sources of unbiased data for understanding T-cell activation. Lack of full concordance of these datasets has illustrated that important facets of T-cell activation are controlled at the level of translation. We undertook translatome analysis of CD8 T-cell activation, combining polysome profiling and microarray analysis. We revealed that altering T-cell receptor stimulation influenced recruitment of mRNAs to heavy polysomes and translation of subsets of genes. A major pathway that was compromised, when TCR signaling was suboptimal, was linked to ribosome biogenesis, a rate-limiting factor in both cell growth and proliferation. Defective TCR signaling affected transcription and processing of ribosomal RNA precursors, as well as the translation of specific ribosomal proteins and translation factors. Mechanistically, IL-2 production was compromised in weakly stimulated T cells, affecting the abundance of Myc protein, a known regulator of ribosome biogenesis. Consequently, weakly activated T cells showed impaired production of ribosomes and a failure to maintain proliferative capacity after stimulation. We demonstrate that primary T cells respond to various environmental cues by regulating ribosome biogenesis and mRNA translation at multiple levels to sustain proliferation and differentiation.

show abstract

“…4F). In some cell types, eIF6 downmodulation can cause a reduced G1/S phase progression and impaired proliferation (Miluzio et al, 2015;Ricciardi et al, 2015). To exclude the possibility that the effects of eIF6 depletion on acquisition of effector functions in T cells were an indirect outcome of defective proliferation, we evaluated the percentage of cells entering the cell cycle by carboxyfluorescein succinimidyl ester (CFSE) analysis.…”

Section: Eif6 Downregulation In Human Cd4 + T Cells Affects Proper Acmentioning

confidence: 99%

High levels of eukaryotic Initiation Factor 6 (eIF6) are required for immune system homeostasis and for steering the glycolytic flux of TCR-stimulated CD4+ T cells in both mice and humans

Manfrini

Ricciardi

Miluzio

et al. 2017

Developmental & Comparative Immunology

View full text Add to dashboard Cite

Eukaryotic Initiation Factor 6 (eIF6) is required for 60S ribosomal subunit biogenesis and efficient initiation of translation. Intriguingly, in both mice and humans, endogenous levels of eIF6 are detrimental as they act as tumor and obesity facilitators, raising the question on the evolutionary pressure that maintains high eIF6 levels. Here we show that, in mice and humans, high levels of eIF6 are required for proper immune functions. First, eIF6 heterozygous (het) mice show an increased mortality during viral infection and a reduction of peripheral blood CD4 Effector Memory T cells. In human CD4 T cells, eIF6 levels rapidly increase upon T-cell receptor activation and drive the glycolytic switch and the acquisition of effector functions. Importantly, in CD4 T cells, eIF6 levels control interferon-γ (IFN-γ) secretion without affecting proliferation. In conclusion, the immune system has a high evolutionary pressure for the maintenance of a dynamic and powerful regulation of the translational machinery.

show abstract

Eukaryotic translation initiation factor 6 is a novel regulator of reactive oxygen species‐dependent megakaryocyte maturation

Cited by 13 publications

References 52 publications

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

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

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

High levels of eukaryotic Initiation Factor 6 (eIF6) are required for immune system homeostasis and for steering the glycolytic flux of TCR-stimulated CD4+ T cells in both mice and humans

Contact Info

Product

Resources

About