ABSTRACT

BMP2K (BMP2 inducible kinase) is a serine-threonine kinase with high amino acid homology to a known endocytic regulator, AAK1, and thus has been suspected to act in endocytosis. In our recent study, we report that BMP2K kinase regulates erythroid maturation in a manner that could not be explained by its involvement in endocytosis. Instead, we discovered that in erythroid cells, its splicing variants (BMP2K-L and BMP2K-S) act in opposing ways to regulate autophagic degradation, an important event in erythroid maturation. We also found that both isoforms could interact with a mammalian counterpart of yeast Sec16, SEC16A, a regulator of COPII vesicle-dependent secretory trafficking. BMP2K-L and -S differentially affect SEC16A levels and distribution, as well as abundance of SEC31A at COPII assemblies (SEC31A load). The regulation of SEC31A load by BMP2K variants concerned assemblies positive for SEC24B, a SEC16A interactor implicated in macroautophagy/autophagy. Hence, we found an unusual mechanism of two splicing variants of a kinase playing opposing roles in autophagy, potentially via differential regulation of SEC16A-dependent COPII assembly. Thereby they constitute a regulatory system, that we call the BMP2K-L/S system, fine-tuning autophagy and modulating erythroid maturation.

摘要

BMP2K（BMP2 诱导激酶）是一种丝氨酸-苏氨酸激酶，与已知的内吞调节因子 AAK1 具有高度的氨基酸同源性，因此被怀疑在内吞作用中起作用。在我们最近的研究中，我们报告说 BMP2K 激酶以一种无法通过其参与内吞作用来解释的方式调节红细胞成熟。相反，我们发现在类红细胞中，其剪接变体（BMP2K-L 和 BMP2K-S）以相反的方式调节自噬降解，这是红细胞成熟中的一个重要事件。我们还发现这两种亚型都可以与酵母 Sec16 的哺乳动物对应物 SEC16A 相互作用，SEC16A 是 COPII 囊泡依赖性分泌运输的调节剂。BMP2K-L 和 -S 不同地影响 SEC16A 水平和分布，以及 COPII 组件（SEC31A 负载）中 SEC31A 的丰度。BMP2K 变体对 SEC31A 负载的调节涉及对 SEC24B 呈阳性的组件，SEC24B 是一种与巨自噬/自噬有关的 SEC16A 相互作用物。因此，我们发现了一种激酶的两种剪接变体在自噬中发挥相反作用的不寻常机制，可能是通过 SEC16A 依赖性 COPII 组装的差异调节。因此它们构成了一个调节系统，我们称之为 BMP2K-L/S 系统，微调自噬和调节红细胞成熟。