IIMCB researchers from the Laboratory of Cell Biology uncover a novel molecular regulatory system constituted by two splicing variants of BMP2K kinase playing opposing roles in intracellular membrane trafficking and red blood cell maturation.
Although red blood cell production (erythropoiesis) is absolutely indispensable for humans and animals, its molecular mechanisms and regulation are not fully understood. Defective erythropoiesis underlies development of anemia and some myeloproliferative disorders, both of which represent a big problem in the clinic. In a recent study published in eLife, Jarosław Cendrowski, Marta Miączyńska and their co-workers from the Laboratory of Cell Biology of IIMCB report the identification of a novel molecular regulatory system that controls maturation of red blood precursor cells. The discovered BMP2K-L/S system, via controlling intracellular membrane trafficking events, potentially regulates the efficiency of red blood cell production and may be implicated in leukemogenesis. The study was performed with help of researchers from the Nencki Institute.
During erythropoiesis, red blood precursor cells undergo profound rearrangements of membrane transport pathways, including remodeling of their plasma membrane proteome, via exocytosis and endocytosis, as well as removal of intracellular organelles, by autophagic clearance. Such intense changes require existence of erythroid-specific mechanisms and regulators of membrane trafficking which however are still poorly characterized. Dr Cendrowski and Prof. Miączyńska found a novel erythroid specific regulator of membrane transport, BMP2K kinase which emerges to function at the crossroad between endocytic, secretory and autophagic pathways.
Miączyńska’s lab has been long studying the involvement of endocytic trafficking in health and disease. Although BMP2K has been suspected to regulate endocytosis, its cellular functions were ill-defined. In their newest work, the scientists discover a complex regulatory nexus composed of two splicing variants of BMP2K, both of which are transiently enriched during differentiation of red blood cell precursors. The study shows that in the erythroid lineage the intracellular role of this kinase extends beyond endocytosis, uncovering an unusual mechanism wherein its longer (BMP2K-L) and shorter (BMP2K-S) splicing variants have opposing effects on assembly of COPII early secretory structures and on autophagic degradation.
Based on publicly available gene expression data, the researchers discovered that the gene encoding BMP2K kinase is particularly active during erythropoiesis. However, careful analysis of cells from subsequent stages of mouse erythropoiesis (erythroblasts) showed that levels of the two BMP2K splicing variants although initially upregulated are subsequently downregulated during this process. In addition erythroblast maturation is associated with increasing proportion between the abundance of BMP2K-L and -S. In vitro experiments further showed that BMP2K-L and BMP2K-S have opposing effects on erythroid maturation that could be due to differential regulation of SEC16A-dependent COPII assembly and autophagy, processes crucial for erythropoiesis. Specifically, BMP2K-L promotes COPII assembly, autophagic degradation and erythroid maturation, while BMP2K-S is an inhibitor of these processes.
The results of this research lay grounds for studying whether pharmacological modulation of the BMP2K-L/S system function could be beneficial for patients suffering from anemia or leukemia.
See full article: Splicing variation of BMP2K balances abundance of COPII assemblies and autophagic degradation in erythroid cells, Jarosław Cendrowski, Marta Kaczmarek, Michał Mazur, Katarzyna Kuźmicz-Kowalska, Kamil Jastrzębski, Marta Brewińska-Olchowik, Agata Kominek, Katarzyna Piwocka, Marta Miączyńska
