Splicing variants of an endocytic regulator, BMP2K, differentially control autophagic degradation in erythroid cells

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.