Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia 5000, Australia.
School of Medicine, University of Adelaide, Adelaide, South Australia 5005, Australia.
Nat Commun. 2016 Oct 27;7:13198. doi: 10.1038/ncomms13198.
Cross-linkage of the high-affinity immunoglobulin E (IgE) receptor (FcɛRI) on mast cells by antigen ligation has a critical role in the pathology of IgE-dependent allergic disorders, such as anaphylaxis and asthma. Restraint of intracellular signal transduction pathways that promote release of mast cell-derived pro-inflammatory mediators is necessary to dampen activation and restore homoeostasis. Here we show that the ligase Nedd4-2 and the adaptor Ndfip1 (Nedd4 family interacting protein 1) limit the intensity and duration of IgE-FcɛRI-induced positive signal transduction by ubiquitinating phosphorylated Syk, a tyrosine kinase that is indispensable for downstream FcɛRI signalosome activity. Importantly, loss of Nedd4-2 or Ndfip1 in mast cells results in exacerbated and prolonged IgE-mediated cutaneous anaphylaxis in vivo. Our findings reveal an important negative regulatory function for Nedd4-2 and Ndfip1 in IgE-dependent mast cell activity.
交联高亲和力免疫球蛋白 E (IgE) 受体 (FcɛRI) 与抗原的连接在 IgE 依赖性过敏疾病（如过敏反应和哮喘）的发病机制中起着关键作用。抑制促进肥大细胞来源的促炎介质释放的细胞内信号转导途径对于抑制激活和恢复体内平衡是必要的。在这里，我们发现连接酶 Nedd4-2 和衔接蛋白 Ndfip1（Nedd4 家族相互作用蛋白 1）通过泛素化磷酸化的 Syk（一种酪氨酸激酶，对于下游 FcɛRI 信号体的活性是不可或缺的）来限制 IgE-FcɛRI 诱导的正信号转导的强度和持续时间。重要的是，肥大细胞中 Nedd4-2 或 Ndfip1 的缺失会导致体内 IgE 介导的皮肤过敏反应加剧和延长。我们的研究结果揭示了 Nedd4-2 和 Ndfip1 在 IgE 依赖性肥大细胞活性中的重要负调节功能。
