Search

Intracellular transport undergoes remodeling upon cell differentiation, which involves cell type-specific regulators. Bone morphogenetic protein 2-inducible kinase (BMP2K) has been potentially implicated in endocytosis and cell differentiation but its molecular functions remained unknown. We discovered that its longer (L) and shorter (S) splicing variants regulate erythroid differentiation in a manner unexplainable by their involvement in AP-2 adaptor phosphorylation and endocytosis. However, both variants interact with SEC16A and could localize to the juxtanuclear secretory compartment. Variant-specific depletion approach showed that BMP2K isoforms constitute a BMP2K-L/S regulatory system that controls the distribution of SEC16A and SEC24B as well as SEC31A abundance at COPII assemblies. Finally, we found L to promote and S to restrict autophagic degradation and erythroid differentiation. Hence, we propose that BMP2K-L and BMP2K-S differentially regulate abundance and distribution of COPII assemblies as well as autophagy, possibly thereby fine-tuning erythroid differentiation.

Membrane and secretory proteins are essential for almost every aspect of cellular function. These proteins are incorporated into ER-derived carriers and transported to the Golgi before being sorted for delivery to their final destination. Although ER-to-Golgi trafficking is highly conserved among eukaryotes, several layers of complexity have been added to meet the increased demands of complex cell types in metazoans. The specialized morphology of neurons and the necessity for precise spatiotemporal control over membrane and secretory protein localization and function make them particularly vulnerable to defects in trafficking. This review summarizes the general mechanisms involved in ER-to-Golgi trafficking and highlights mutations in genes affecting this process, which are associated with neurological diseases in humans.

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. [ABSTRACT FROM AUTHOR]

Membrane and secretory proteins are essential for almost every aspect of cellular function. These proteins are incorporated into ER-derived carriers and transported to the Golgi before being sorted for delivery to their final destination. Although ER-to-Golgi trafficking is highly conserved among eukaryotes, several layers of complexity have been added to meet the increased demands of complex cell types in metazoans. The specialized morphology of neurons and the necessity for precise spatiotemporal control over membrane and secretory protein localization and function make them particularly vulnerable to defects in trafficking. This review summarizes the general mechanisms involved in ER-to-Golgi trafficking and highlights mutations in genes affecting this process, which are associated with neurological diseases in humans. [ABSTRACT FROM AUTHOR]