NEUROBEACHIN regulates hematopoietic progenitor differentiation and survival by modulating NOTCH activity.
Miguel GanuzaAntonio Morales-HernandezAlanna Van HuizenAshley ChabotTrent HallClaire CaprioDavid FinkelsteinShannon L McKinney FreemanPublished in: Blood advances (2024)
Hematopoietic stem cells (HSCs) can generate all blood cells. This ability is exploited in HSC transplantation (HSCT) to treat hematologic disease. A clear understanding of the molecular mechanisms that regulate HSCT is necessary to continue improving transplant protocols. We identified the BEACH-domain containing protein (BDCP), NEUROBEACHIN (NBEA), as a putative regulator of HSCT. Here, we demonstrated that NBEA and related BDCPs, including LRBA, NBEAL1 and LYST, are required during HSCT to efficiently reconstitute the hematopoietic system of lethally irradiated mice. Nbea knockdown in mouse HSCs induced apoptosis and a differentiation block post-transplantation. Nbea deficiency in hematopoietic progenitor cells perturbed the expression of genes implicated in vesicle trafficking and led to changes in NOTCH receptor localization. This resulted in perturbation of the NOTCH transcriptional program, which is required for efficient HSC engraftment. In sum, our findings reveal a novel role for NBEA in the control of NOTCH receptor turnover in hematopoietic cells and supports a model where BDCP regulated vesicle trafficking is required for efficient HSCT.
Keyphrases
- induced apoptosis
- hematopoietic stem cell
- endoplasmic reticulum stress
- signaling pathway
- bone marrow
- oxidative stress
- stem cells
- cell proliferation
- cell cycle arrest
- binding protein
- genome wide
- cell therapy
- gene expression
- pi k akt
- type diabetes
- cell death
- protein protein
- metabolic syndrome
- single cell
- small molecule
- smoking cessation
- replacement therapy
- free survival
- cell fate
- heat shock protein