The Neurobeachin‐like 2 protein (NBEAL2) controls the homeostatic level of the ribosomal protein RPS6 in mast cells

Author:

Wegner Philine1,Drube Julia2,Ziegler Lisa1,Strotmann Birgit1,Marquardt Raphaela1,Küchler Claudia1,Groth Marco3,Nieswandt Bernhard4,Andreas Nico1ORCID,Drube Sebastian1ORCID

Affiliation:

1. Institut für Immunologie Friedrich‐Schiller‐Universität Jena, Universitätsklinikum Jena Jena Germany

2. Institut für Molekulare Zellbiologie Friedrich‐Schiller‐Universität Jena, Universitätsklinikum Jena Jena Germany

3. CF Next‐Generation Sequencing Fritz Lipmann Institute Jena Germany

4. Institute of Experimental Biomedicine University Hospital Würzburg and Rudolf Virchow Center for Integrative and Translational Bioimaging Würzburg Germany

Abstract

AbstractThe Beige and Chediak‐Higashi (BEACH) domain‐containing, Neurobeachin‐like 2 (NBEAL2) protein is a molecule with a molecular weight of 300 kDa. Inactivation of NBEAL2 by loss‐of‐function mutations in humans as well as deletion of the Nbeal2 gene in mice results in functional defects in cells of the innate immune system such as neutrophils, NK‐cells, megakaryocytes, platelets and of mast cells (MCs). To investigate the detailed function of NBEAL2 in murine MCs we generated MCs from wild type (wt) and Nbeal2−/− mice, and deleted Nbeal2 by CRISPR/Cas9 technology in the murine mast cell line MC/9. We also predicted the structure of NBEAL2 to infer its function and to examine potential mechanisms for its association with interaction partners by using the deep learning‐based method RoseTTAFold and the Pymol© software. The function of NBEAL2 was analysed by molecular and immunological techniques such as co‐immunoprecipitation (co‐IP) experiments, western blotting, enzyme‐linked immunosorbent assay and flow cytometry. We identified RPS6 as an interaction partner of NBEAL2. Thereby, the NBEAL2/RPS6 complex formation is probably required to control the protein homeostasis of RPS6 in MCs. Consequently, inactivation of NBEAL2 leads to accumulation of strongly p90RSK‐phosphorylated RPS6 molecules which results in the development of an abnormal MC phenotype characterised by prolonged growth factor‐independent survival and in a pro‐inflammatory MC‐phenotype.

Funder

Bundesministerium für Bildung und Forschung

Publisher

Wiley

Subject

Immunology,Immunology and Allergy

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