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 language | English |
|---|---|
| Pages (from-to) | 2108-2118 |
| Number of pages | 11 |
| Journal | Journal of Thrombosis and Haemostasis |
| Volume | 13 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Nov 1 2015 |
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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 journal › Article
}
TY - JOUR
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.
PY - 2015/11/1
Y1 - 2015/11/1
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.
KW - Initiation factors
KW - Megakaryocytes
KW - Platelets
KW - Reactive oxygen species
KW - Thrombocytopenia
UR - http://www.scopus.com/inward/record.url?scp=84946574802&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84946574802&partnerID=8YFLogxK
U2 - 10.1111/jth.13150
DO - 10.1111/jth.13150
M3 - Article
C2 - 26391622
AN - SCOPUS:84946574802
VL - 13
SP - 2108
EP - 2118
JO - Journal of Thrombosis and Haemostasis
JF - Journal of Thrombosis and Haemostasis
SN - 1538-7933
IS - 11
ER -