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

S. Ricciardi, A. Miluzio, D. Brina, K. Clarke, M. Bonomo, R. Aiolfi, L. G. Guidotti, F. Falciani, S. Biffo

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Background: Ribosomopathies constitute a class of inherited disorders characterized by defects in ribosome biogenesis and function. Classically, bone marrow (BM) failure is a clinical symptom shared between these syndromes, including Shwachman-Bodian-Diamond syndrome (SBDS). Eukaryotic translation initiation factor 6 (eIF6) is a critical translation factor that rescues the quasilethal effect of the loss of the SBDS protein. Objectives: To determine whether eIF6 activity is necessary for BM development. Methods: We used eIF6+/- mice and primary BM megakaryocytes to investigate the involvement of eIF6 in the regulation of hematopoiesis. Results: We provide evidence that reduced eIF6 expression negatively impacts on megakaryopoiesis. We show that inhibition of eIF6 leads to a reduction in cell size and mean ploidy level of megakaryocytes and a delay in megakaryocyte maturation by blocking the G1/S transition. Consistent with this phenotype, only few megakaryocyte-forming proplatelets were found in eIF6+/- cells. We also discovered that, in eIF6+/- cells, the steady-state abundance of mitochondrial respiratory chain complex I-encoding mRNAs is decreased, resulting in decreased reactive oxygen species (ROS) production. Intriguingly, connectivity map analysis showed that eIF6-mediated changes overlap with specific translational inhibitors. eIF6 is a translation factor acting downstream of insulin/phorbol 12-myristate 13-acetate (PMA) stimulation. PMA treatment significantly restored eIF6+/- megakaryocyte maturation, indicating that activation of eIF6 is essential for the rescue of the phenotype. Conclusions: Taken together, our results show a role for eIF6-driven translation in megakaryocyte development, and unveil the novel connection between translational control and ROS production in this cell subset.

Original languageEnglish
Pages (from-to)2108-2118
Number of pages11
JournalJournal of Thrombosis and Haemostasis
Volume13
Issue number11
DOIs
Publication statusPublished - Nov 1 2015

Fingerprint

Eukaryotic Initiation Factors
Megakaryocytes
Reactive Oxygen Species
Bone Marrow
eIF-6
Acetates
Electron Transport Complex I
Phenotype
Ploidies
Bone Development
Hematopoiesis
Electron Transport
Ribosomes
Cell Size

Keywords

  • Initiation factors
  • Megakaryocytes
  • Platelets
  • Reactive oxygen species
  • Thrombocytopenia

ASJC Scopus subject areas

  • Hematology

Cite this

Eukaryotic translation initiation factor 6 is a novel regulator of reactive oxygen species-dependent megakaryocyte maturation. / Ricciardi, S.; Miluzio, A.; Brina, D.; Clarke, K.; Bonomo, M.; Aiolfi, R.; Guidotti, L. G.; Falciani, F.; Biffo, S.

In: Journal of Thrombosis and Haemostasis, Vol. 13, No. 11, 01.11.2015, p. 2108-2118.

Research output: Contribution to journalArticle

Ricciardi, S. ; Miluzio, A. ; Brina, D. ; Clarke, K. ; Bonomo, M. ; Aiolfi, R. ; Guidotti, L. G. ; Falciani, F. ; Biffo, S. / Eukaryotic translation initiation factor 6 is a novel regulator of reactive oxygen species-dependent megakaryocyte maturation. In: Journal of Thrombosis and Haemostasis. 2015 ; Vol. 13, No. 11. pp. 2108-2118.
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abstract = "Background: Ribosomopathies constitute a class of inherited disorders characterized by defects in ribosome biogenesis and function. Classically, bone marrow (BM) failure is a clinical symptom shared between these syndromes, including Shwachman-Bodian-Diamond syndrome (SBDS). Eukaryotic translation initiation factor 6 (eIF6) is a critical translation factor that rescues the quasilethal effect of the loss of the SBDS protein. Objectives: To determine whether eIF6 activity is necessary for BM development. Methods: We used eIF6+/- mice and primary BM megakaryocytes to investigate the involvement of eIF6 in the regulation of hematopoiesis. Results: We provide evidence that reduced eIF6 expression negatively impacts on megakaryopoiesis. We show that inhibition of eIF6 leads to a reduction in cell size and mean ploidy level of megakaryocytes and a delay in megakaryocyte maturation by blocking the G1/S transition. Consistent with this phenotype, only few megakaryocyte-forming proplatelets were found in eIF6+/- cells. We also discovered that, in eIF6+/- cells, the steady-state abundance of mitochondrial respiratory chain complex I-encoding mRNAs is decreased, resulting in decreased reactive oxygen species (ROS) production. Intriguingly, connectivity map analysis showed that eIF6-mediated changes overlap with specific translational inhibitors. eIF6 is a translation factor acting downstream of insulin/phorbol 12-myristate 13-acetate (PMA) stimulation. PMA treatment significantly restored eIF6+/- megakaryocyte maturation, indicating that activation of eIF6 is essential for the rescue of the phenotype. Conclusions: Taken together, our results show a role for eIF6-driven translation in megakaryocyte development, and unveil the novel connection between translational control and ROS production in this cell subset.",
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T1 - Eukaryotic translation initiation factor 6 is a novel regulator of reactive oxygen species-dependent megakaryocyte maturation

AU - Ricciardi, S.

AU - Miluzio, A.

AU - Brina, D.

AU - Clarke, K.

AU - Bonomo, M.

AU - Aiolfi, R.

AU - Guidotti, L. G.

AU - Falciani, F.

AU - Biffo, S.

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N2 - Background: Ribosomopathies constitute a class of inherited disorders characterized by defects in ribosome biogenesis and function. Classically, bone marrow (BM) failure is a clinical symptom shared between these syndromes, including Shwachman-Bodian-Diamond syndrome (SBDS). Eukaryotic translation initiation factor 6 (eIF6) is a critical translation factor that rescues the quasilethal effect of the loss of the SBDS protein. Objectives: To determine whether eIF6 activity is necessary for BM development. Methods: We used eIF6+/- mice and primary BM megakaryocytes to investigate the involvement of eIF6 in the regulation of hematopoiesis. Results: We provide evidence that reduced eIF6 expression negatively impacts on megakaryopoiesis. We show that inhibition of eIF6 leads to a reduction in cell size and mean ploidy level of megakaryocytes and a delay in megakaryocyte maturation by blocking the G1/S transition. Consistent with this phenotype, only few megakaryocyte-forming proplatelets were found in eIF6+/- cells. We also discovered that, in eIF6+/- cells, the steady-state abundance of mitochondrial respiratory chain complex I-encoding mRNAs is decreased, resulting in decreased reactive oxygen species (ROS) production. Intriguingly, connectivity map analysis showed that eIF6-mediated changes overlap with specific translational inhibitors. eIF6 is a translation factor acting downstream of insulin/phorbol 12-myristate 13-acetate (PMA) stimulation. PMA treatment significantly restored eIF6+/- megakaryocyte maturation, indicating that activation of eIF6 is essential for the rescue of the phenotype. Conclusions: Taken together, our results show a role for eIF6-driven translation in megakaryocyte development, and unveil the novel connection between translational control and ROS production in this cell subset.

AB - Background: Ribosomopathies constitute a class of inherited disorders characterized by defects in ribosome biogenesis and function. Classically, bone marrow (BM) failure is a clinical symptom shared between these syndromes, including Shwachman-Bodian-Diamond syndrome (SBDS). Eukaryotic translation initiation factor 6 (eIF6) is a critical translation factor that rescues the quasilethal effect of the loss of the SBDS protein. Objectives: To determine whether eIF6 activity is necessary for BM development. Methods: We used eIF6+/- mice and primary BM megakaryocytes to investigate the involvement of eIF6 in the regulation of hematopoiesis. Results: We provide evidence that reduced eIF6 expression negatively impacts on megakaryopoiesis. We show that inhibition of eIF6 leads to a reduction in cell size and mean ploidy level of megakaryocytes and a delay in megakaryocyte maturation by blocking the G1/S transition. Consistent with this phenotype, only few megakaryocyte-forming proplatelets were found in eIF6+/- cells. We also discovered that, in eIF6+/- cells, the steady-state abundance of mitochondrial respiratory chain complex I-encoding mRNAs is decreased, resulting in decreased reactive oxygen species (ROS) production. Intriguingly, connectivity map analysis showed that eIF6-mediated changes overlap with specific translational inhibitors. eIF6 is a translation factor acting downstream of insulin/phorbol 12-myristate 13-acetate (PMA) stimulation. PMA treatment significantly restored eIF6+/- megakaryocyte maturation, indicating that activation of eIF6 is essential for the rescue of the phenotype. Conclusions: Taken together, our results show a role for eIF6-driven translation in megakaryocyte development, and unveil the novel connection between translational control and ROS production in this cell subset.

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KW - Thrombocytopenia

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