# Nbeal2 Inactivation Triggers Abl1 Stabilisation and Dysregulated Subcellular Localisation of the Multi‐Drug‐Resistant Protein MDR1 (ABCB1) in Mast Cells

## TL;DR

This paper shows that inactivating NBEAL2 in mast cells leads to increased surface expression of the drug-resistant protein ABCB1, affecting cell function and stability.

## Contribution

The study reveals a novel mechanism linking NBEAL2 inactivation to Abl1 stabilization and ABCB1 dysregulation in mast cells.

## Key findings

- NBEAL2 inactivation stabilizes Abl1, contributing to mast cell degeneration.
- NBEAL2 promotes ABCB1 granule stability and prevents its membrane translocation.
- IL-33 activates TAK1-IKK2 and Src-family kinases to counteract ABCB1 upregulation.

## Abstract

Inactivation of the BEACH (beige and chediak‐higashi) family member NBEAL2 in humans and mice results in the development of the gray platelet syndrome (GPS), a bleeding disorder characterised by macrothrombocytopenia and splenomegaly. On the cellular level, NBEAL2 inactivation leads to functional defects in megakaryocytes, platelets, neutrophils and NK cells. In addition, Nbeal2 deletion in mice causes specific defects in mast cells (MCs), such as accumulation of transcription factors and proteins that are involved in the protein biosynthesis machinery. These defects culminate in non‐physiological survival behaviour and an amplified stem cell factor (SCF)‐, interleukin (IL)‐3‐ and IL‐33‐induced cytokine production. Here we show that NBEAL2 deficiency also leads to an Abl1‐supported increased surface expression of the multi‐drug‐resistant protein 1 (Mdr‐1) ABCB1, which is antagonised by the IL‐33‐induced activation of the TAK1‐IKK2 module and the activation of Src‐family‐kinases (SFKs). Our data demonstrate that NBEAL2 is required to control the surface expression of ABCB1.

(A) Proposed model for Abl1 degradation via Nbeal2. Nbeal2 interacts with Abl1 with its WDR domain. This results in proteasomal degradation by a yet unidentified ubiquitin ligase. Therefore, Nbeal2 inactivation stabilises Abl1, which supports mast cell (MC) degeneration. (B) In wt MCs, the Abl1 protein level is controlled by Nbeal2. Furthermore, Nbeal2 promotes the generation and stability of ABCB1‐loaded MC granules within wt MCs. In Nbeal2
−/− MCs the stability of ABCB1‐loaded granules is decreased and the translocation of ABCB1 to the cell membrane is supported by stabilised Abl1.