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BMP2K is an inhibitor of erythroid differentiation that restricts endocytosis and SEC16A-dependent autophagy

ABSTRACT: Coordination of membrane-related processes inside the cells is facilitated by proteins regulating multiple vesicular trafficking pathways. Bone morphogenetic protein 2-inducible kinase (BMP2K) is a poorly studied ubiquitous protein with the highest expression in the erythroid lineage. We hypothesized that this kinase, potentially implicated in endocytosis and autophagy, could integrate various trafficking routes. By proximity biotinylation (BioID), we revealed differential association of two BMP2K splicing variants with regulators of clathrin-mediated endocytosis (CME) and with components of early secretory pathway (ESP). We found the longer variant (BMP2K-L) to interact with markers of clathrin-coated pits, REPS1 and phosphorylated μ2 adaptin, and the shorter variant (BMP2K-S) to associate with early secretory compartments positive for ARFGAP1 and SEC16A proteins. Splicing variant-specific RNAi approach in K562 erythroleukemia cells showed that BMP2K-L controls μ2 phosphorylation while BMP2K-S post-transcriptionally maintains SEC16A protein levels. Depleting all BMP2K splicing variants promoted autophagic degradation via a functional crosstalk with SEC16A, enhanced transferrin endocytosis, and erythroid differentiation. We propose that, owing to alternative splicing, BMP2K gene products restrict erythroid differentiation coordinating endocytosis and SEC16A-dependent autophagy.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Suspension Culture, Permanent Cell Line Cell

SUBMITTER: Jaroslaw Cendrowski

LAB HEAD: Marta Miaczynska

PROVIDER: PXD013542 | Pride | 2019-07-31

REPOSITORIES: Pride

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Publications

Splicing variation of BMP2K balances abundance of COPII assemblies and autophagic degradation in erythroid cells.

Cendrowski Jaroslaw J Kaczmarek Marta M Mazur Michał M Kuzmicz-Kowalska Katarzyna K Jastrzebski Kamil K Brewinska-Olchowik Marta M Kominek Agata A Piwocka Katarzyna K Miaczynska Marta M

eLife 20200814

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, bo ...[more]

PMID: 32795391

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Project description:The phylum Apicomplexa comprises an ancient group of early divergent eukaryotes, including some of the most deadly pathogens of medical and veterinary importance. Plasmodium species are responsible for malaria, which causes as many as 700,000 deaths per year, while Toxoplasma gondii chronically infects up to 30% of the human population, with immunocompromised patients and pregnant women at risk for adverse outcomes, such as toxoplasmic encephalitis and spontaneous abortion, respectively. T. gondii is considered a model system not only for its pathogenic relatives but also for intracellular parasitism and infection biology in general. T. gondii has common eukaryotic organelles, including the nucleus, endoplasmic reticulum (ER), and a single Golgi stack, but also specific secretory organelles named dense granules, micronemes, and rhoptries that contain parasite-derived factors required for host infection. Rhoptries and micronemes are formed de novo during parasite replication, and this process requires significant protein and lipid trafficking through the secretory pathway. The trafficking mechanisms employed by T. gondii retain several typical eukaryote components as well as evolving divergent features. Protein trafficking of this parasite is mediated by entry into a canonical ER followed by vesicle packaging through a single Golgi complex. Post-Golgi protein sorting to specific organelles requires the function of dynamin-related protein B, which is involved in fission events. Downstream Rab-GTPases function throughout the parasite secretory pathway. T. gondii soluble N-ethylmaleimide-sensitive-factor attachment protein receptor (SNARE) proteins in docking and fusion at target membranes have also been described. However, unlike in mammalian cells, T. gondii ER is reduced so that the nuclear envelope itself contributes to a substantial proportion of its total volume. Whereas in mammalian cells hundreds of Golgi stacks occupy the perinuclear area, the Golgi apparatus is limited to a single discrete structure in T.gondii. The post-Golgi system also named the endosome-like compartment (ELC) is involved in the trafficking of microneme proteins. The ELC is decorated by the small GTPases, Rab5 and Rab7, which are typically associated with the endosomal system. Nevertheless, classical endocytosis has not yet been validated in T. gondii. This parasite has no lysosomes; rather the parasite harbors acidic vesicles that were thought to be precursors of the rhoptry organelles. The parasite lacks most components of endosomal sorting complexes (ESCRT), which are known for their roles in forming multivesicular bodies that deliver ubiquitinated membrane proteins and lipids to lysosomes for degradation. The machinery required for caveogenesis and caveola-dependent invaginations have not yet been identified in the parasite. Furthermore, while evidence of conventional clathrin-dependent endocytosis by T.gondii is lacking, clathrin is present exclusively in post-Golgi compartments where its function is restricted to post-Golgi trafficking, and the uptake of cytosol proteins by the tachyzoites of T. gondii has recently been described using an endocytosis assay. However, the mechanisms underlying the events of this unconventional endocytosis in the parasite remain to be determined. Clearly, the secretory pathway of T. gondii can be considered a stripped-down version of the more complex trafficking machinery that characterizes higher eukaryotes. Despite this minimal trafficking machinery, the parasites actively rely on a membrane vesicle formation and transport during its intracellular lifecycle; however, to date, comparatively little is known about the mechanisms involved in trafficking pathways in T. gondii. We previously reported a T. gondii sortilin-like receptor (TgSORTLR) that regulates protein transport and is essential for apical secretory organelle biogenesis and host infection17. Moreover, the C-terminal tail of TgSORTLR was shown to be involved in recruiting many cytosolic cargo proteins including two homologues of the core retromer components, Vps26 and Vps35, which are known to regulate retrograde transport from endosomes to the trans-Golgi Network (TGN) in yeast and mammals. Here, we report that a singular architecture with a trimer Vps35-Vps26-Vps29 core complex acts as the major cargo endosomal recycling machinery and is required for parasite integrity and more specifically for secretory organelle biogenesis and maintenance of a multiple ligand-binding transporter at the T. gondii membrane. Our findings provide strong evidence that the unconventional TgSORTLR-containing endosome-like compartment is involved in distinct mechanisms for the delivery of major retromer-dependent cargo. In this current work, we demonstrate a definitive role for the endocytic recycling pathway in T. gondii pathogenesis.

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