西湖高等研究院施一公研究小组在研究中取得进展。他们的研究发现了IgE介导FcεRI活化的分子机制。相关论文于2024年10月23日发表在《自然》杂志上。

本研究表明，在IgE结合之前，FcεRI主要以二聚体形式存在于人肥大细胞膜上。人类FcεRI的结构为二聚体，每个启动子由一个α亚基、一个β亚基和两个γ亚基组成。α亚基的跨膜螺旋与γ和β亚基的跨膜螺旋呈层状排列。二聚体界面是由细胞内近膜区域的α和γ亚基的四螺旋束介导的。

嵌入跨膜结构域的胆固醇样分子可以稳定二聚体组装。在IgE结合后，二聚体FcεRI解离成两个原体，每个原体与一个IgE分子结合。重要的是，这一过程引发了大鼠嗜碱性细胞中Egr1/3和Ccl2的转录激活，这可以通过抑制FcεRI二聚体到单体的转变来减弱。总的来说，他们的研究揭示了抗原不依赖、IgE介导的FcεRI激活的机制。

据悉，过敏性疾病影响着工业化国家四分之一以上的人，已成为重大的公共卫生问题。IgE的高亲和Fc受体（Fcε RI）主要存在于肥大细胞和嗜碱性细胞中，在过敏性疾病中起重要作用。单体IgE结合FcεRI调控肥大细胞的存活、分化和成熟。然而，潜在的分子机制尚不清楚。

附：英文原文

Title: Molecular mechanism of IgE-mediated FcεRI activation

Author: Chen, Mengying, Su, Qiang, Shi, Yigong

Issue&Volume: 2024-10-23

Abstract: Allergic diseases, affecting over a quarter of individuals in industrialized countries, have become significant public health concerns1,2. The high-affinity Fc receptor for IgE (FcεRI), mainly present on mast cells and basophils, plays a crucial role in allergic diseases3-5. Monomeric IgE binding to FcεRI regulates mast cell survival, differentiation, and maturation6-8. However, the underlying molecular mechanism remains unclear. Here we demonstrate that, prior to IgE binding, FcεRI mostly exists as a homo-dimer on human mast cell membrane. The structure of human FcεRI confirms the dimeric organization, with each promoter comprising one α subunit, one β subunit, and two γ subunits. The transmembrane helices of the α subunits form a layered arrangement with those of the γ and β subunits. The dimeric interface is mediated by a four-helix bundle of the α and γ subunits at the intracellular juxtamembrane region. Cholesterol-like molecules embedded within the transmembrane domain may stabilize the dimeric assembly. Upon IgE binding, the dimeric FcεRI dissociates into two protomers, each binding to an IgE molecule. Importantly, this process elicits transcriptional activation of Egr1/3 and Ccl2 in rat basophils, which can be attenuated by inhibiting the FcεRI dimer-to-monomer transition. Collectively, our study unveils the mechanism of antigen-independent, IgE-mediated FcεRI activation.

DOI: 10.1038/s41586-024-08229-8

Source: https://www.nature.com/articles/s41586-024-08229-8