Splicing variation of BMP2K balances endocytosis, COPII trafficking and autophagy in erythroid cells

Abstract

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 interacted with SEC16A whose silencing in K562 erythroid leukemia cells affected generation of COPII assemblies and induced autophagic degradation. Variant-specific depletion approach showed that BMP2K isoforms constitute a BMP2K-L/S regulatory system. Therein, L promotes while S restricts recruitment of SEC31A to SEC24B-containing COPII structures forming at SEC16A-positive ER exit sites. Finally, we found L to promote and S to restrict autophagic degradation. Hence, we propose that BMP2K-L favors SEC16A-dependent intracellular processes important for erythroid maturation, such as COPII trafficking and autophagy, in a manner inhibited by BMP2K-S.