Molecular mechanism of IgE-mediated FcεRI activation

Affiliations

• Research Center for Industries of the Future, Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Institute of Biology, Westlake Institute for Advanced Study, Xihu District, Hangzhou, Zhejiang Province, China
• Westlake Laboratory of Life Sciences and Biomedicine, 18 Shilongshan Road, Xihu District, Hangzhou, Zhejiang Province, China
• Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, School of Medicine, Tsinghua University, Beijing, China

PMID:  #  DOI: 10.1038/s41586-024-08229-8

Abstract

Allergic diseases, affecting over a quarter of individuals in industrialized countries, have become significant public health concerns. The high-affinity Fc receptor for IgE (FcεRI), mainly present on mast cells and basophils, plays a crucial role in allergic diseases. Monomeric IgE binding to FcεRI regulates mast cell survival, differentiation, and maturation6. 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.

过敏性疾病已经成为工业化国家一个重要的公共卫生问题，影响着超过四分之一的人口。高亲和力IgE Fc受体（FcεRI）主要存在于肥大细胞和嗜碱性粒细胞上，FcεRI在过敏疾病中发挥着关键作用。单体IgE与FcεRI结合可以调节肥大细胞的存活、分化和成熟，但其具体分子机制仍不明确。我们的研究发现，在IgE结合之前，FcεRI大多以同源二聚体的形式存在于人类肥大细胞的膜上。人类FcεRI的结构表明其为二聚体，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β和γ亚基的跨膜螺旋形成分层排列，二聚体的相互作用界面由α和γ亚基在细胞内紧邻膜区域的四螺旋束介导。同时，跨膜区域内的类胆固醇分子可能有助于稳定二聚体的结构。在IgE结合后，二聚体FcεRI会解聚成两个单体，每个单体结合一个IgE分子。这一过程还引发了大鼠嗜碱细胞中Egr1/3和Ccl2的转录激活，而抑制FcεRI由二聚体转变为单体的过程则可以减弱这种激活。总体而言，我们的研究揭示了抗原独立的IgE介导的FcεRI激活机制。

关键词：过敏，过敏原，过敏原采购，过敏原购买，过敏检测，过敏原检测，IgE，受体，佰乐博，佰乐博生物