Gene expression analysis of murine wt and Nbeal2 -/- bone marrow derived mast cells (BMMCs) w/o IL-33 treatment. Gene expression analysis of murine wt and Nbeal2 -/- bone marrow derived mast cells (BMMCs) w/o IL-33 treatment

The Neurobeachin-like 2 (Nbeal2) protein is a BEACH (beige and chediak-higashi) family member. Loss of function mutations of the human NBEAL2 gene result in development of the gray platelet syndrome (GPS) a bleeding disorder characterized by macrothrombocytopenia, splenomegaly, and paucity of α-granules in megakaryocytes, platelets, mast cells (MCs), neutrophils and NK cells. We found that Nbeal2 deficiency in MCs leads to an enhanced resistance to growth factor deprivation, dysregulated distribution of c-Kit and of the multidrug resistant protein-1 (ABCB1), as well as to a pro-inflammatory MC-phenotype. These characteristics are caused by a defective protein degradation machinery resulting in accumulation of RSK and ribosomal proteins (RPS). These data demonstrate that Nbeal2 prevents oncogenic transformation by controlling protein homeostasis (proteostasis) in MCs. Overall design: 16 samples in four groups: Nbeal2 -/- w/o IL-33: 4 samples; Nbeal2 -/- with IL-33: 4 samples; wildtype w/o IL-33: 4 samples; wildtype with IL-33: 4 samples.

神经海滩蛋白样2（Nbeal2）蛋白为BEACH（beige与chediak-higashi）家族成员。人类NBEAL2基因的功能丧失性突变可诱发灰色血小板综合征（gray platelet syndrome, GPS），该疾病是一类以巨核细胞、血小板、肥大细胞（mast cells, MCs）、中性粒细胞及自然杀伤细胞（NK细胞）中出现巨血小板减少症、脾脏肿大以及α颗粒匮乏为特征的出血性疾病。本研究发现，肥大细胞中Nbeal2缺失会使其对生长因子剥夺的抗性增强，c-Kit与多药耐药蛋白1（multidrug resistant protein-1, ABCB1）的分布异常，同时呈现促炎性肥大细胞表型。上述特征源于蛋白质降解系统功能缺陷，导致RSK及核糖体蛋白（ribosomal proteins, RPS）蓄积。本研究数据证实，Nbeal2可通过调控肥大细胞内的蛋白质稳态（protein homeostasis, proteostasis）阻止致癌转化。实验整体设计：共设置4组、16个样本，具体分组如下：Nbeal2基因敲除且未添加IL-33组：4个样本；Nbeal2基因敲除且添加IL-33组：4个样本；野生型且未添加IL-33组：4个样本；野生型且添加IL-33组：4个样本。