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

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.