Phosphoinositol-3-Kinase and Heat Shock Cognate B Axis Facilitates Friend of GATA 1 Nuclear Translocation to Promote Erythropoiesis and Megakaryopoiesis

Core Concepts

The PI3K/HSCB axis facilitates the nuclear translocation of the transcription factor FOG1 to promote erythropoiesis and megakaryopoiesis.

Abstract

The article investigates the molecular mechanisms by which signaling pathways regulate key transcription factors controlling erythropoiesis and megakaryopoiesis. The researchers identified heat shock cognate B (HSCB) as an indispensable protein for the nuclear translocation of the transcription factor friend of GATA 1 (FOG1) during erythropoiesis in K562 human erythroleukemia cells and cord-blood-derived human CD34+CD90+ hematopoietic stem cells (HSCs), as well as during megakaryopoiesis of the CD34+CD90+ HSCs.
Mechanistically, the study found that HSCB can be phosphorylated by phosphoinositol-3-kinase (PI3K) to bind with and mediate the proteasomal degradation of transforming acidic coiled-coil containing protein 3 (TACC3), which otherwise detains FOG1 in the cytoplasm, thereby facilitating FOG1 nuclear translocation. Since PI3K is activated during both erythropoiesis and megakaryopoiesis, and FOG1 is a key transcription factor for these processes, the findings elucidate an important, previously unrecognized iron-sulfur cluster delivery independent function of HSCB in regulating erythropoiesis and megakaryopoiesis.

Stats

K562 human erythroleukemia cells and cord-blood-derived human CD34+CD90+ hematopoietic stem cells (HSCs) were used in the study.

Quotes

"HSCB could be phosphorylated by phosphoinositol-3-kinase (PI3K) to bind with and mediate the proteasomal degradation of transforming acidic coiled-coil containing protein 3 (TACC3), which otherwise detained FOG1 in the cytoplasm, thereby facilitating FOG1 nuclear translocation."

Key Insights Distilled From

PI3K/HSCB axis facilitates FOG1 nuclear translocation to promote erythropoiesis and megakaryopoiesis

by Liu,G., Hou,... at www.biorxiv.org 02-06-2024

https://www.biorxiv.org/content/10.1101/2024.02.05.578960v3

Deeper Inquiries

What other signaling pathways or transcription factors might be involved in the regulation of erythropoiesis and megakaryopoiesis besides the PI3K/HSCB/FOG1 axis?

In addition to the PI3K/HSCB/FOG1 axis, several other signaling pathways and transcription factors play crucial roles in the regulation of erythropoiesis and megakaryopoiesis. One significant pathway is the JAK-STAT pathway, which is activated by erythropoietin (EPO) and thrombopoietin (TPO) in erythropoiesis and megakaryopoiesis, respectively. The JAK-STAT pathway regulates the expression of key transcription factors like GATA1, GATA2, and STAT5, which are essential for the differentiation and maturation of erythroid and megakaryocytic lineages. Additionally, the TGF-β pathway, Notch signaling, and Wnt signaling pathways also contribute to the regulation of these hematopoietic processes by modulating the expression and activity of various transcription factors involved in erythropoiesis and megakaryopoiesis.

How might the findings of this study be leveraged to develop new therapeutic approaches for hematological disorders related to erythropoiesis or megakaryopoiesis?

The findings of this study provide valuable insights into the molecular mechanisms underlying erythropoiesis and megakaryopoiesis, highlighting the critical role of HSCB in facilitating FOG1 nuclear translocation through PI3K-mediated phosphorylation. Leveraging this knowledge, novel therapeutic approaches could be developed for hematological disorders associated with aberrant erythropoiesis or megakaryopoiesis. Targeting the PI3K/HSCB/FOG1 axis could offer a promising strategy to modulate erythroid and megakaryocytic differentiation, potentially leading to the development of targeted therapies for conditions such as anemia, thrombocytopenia, and myeloproliferative disorders. By manipulating the interactions between HSCB, TACC3, and FOG1, researchers may uncover new drug targets for hematological disorders and pave the way for more effective treatment options.

What are the potential implications of the iron-sulfur cluster delivery independent function of HSCB discovered in this study for our understanding of the broader roles of HSCB in cellular processes?

The discovery of the iron-sulfur cluster delivery independent function of HSCB in regulating FOG1 nuclear translocation sheds light on the diverse roles of HSCB beyond its canonical function. This finding expands our understanding of the multifaceted roles that HSCB plays in cellular processes, particularly in hematopoiesis. By demonstrating that HSCB can modulate key transcription factors like FOG1 through protein-protein interactions and proteasomal degradation pathways, this study suggests that HSCB may have broader implications in the regulation of gene expression and cell fate determination beyond iron-sulfur cluster delivery. Understanding the non-canonical functions of HSCB could open up new avenues for research into its involvement in other cellular processes and diseases, potentially leading to the development of novel therapeutic interventions targeting HSCB-related pathways in various pathological conditions.