CIN85 regulates the ligand-dependent endocytosis of the IgE receptor: A new molecular mechanism to dampen mast cell function
CIN85 regulates the ligand-dependent endocytosis of the IgE receptor: A new molecular mechanism to dampen mast cell function
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DOI：
10.4049/jimmunol.175.7.4208
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发表时间：
2005-10-01
影响因子：
4.4
通讯作者：
Paolini, R
中科院分区：
文献类型：
--
作者：
Molfetta, R;Belleudi, F;Paolini, R
连接肥大细胞和嗜碱性粒细胞上组成型表达的 IgE (Fc epsilon RI) 高亲和力受体可促进细胞活化并立即释放过敏介质。此外，来自特应性供体的 APC 上的 Fc epsilon RI 上调参与了过敏性疾病的病理生理学。考虑到 IgE 受体的临床相关性，肥大细胞中 Fc epsilon RI 表达的下调可能代表治疗特应性疾病的潜在目标。为了确定参与减弱 Fc epsilon RI 表达和信号传导的新分子机制，我们将注意力集中在 CIN85，这是一种支架分子，与泛素连接酶 Cbl 协同调节网格蛋白介导的几种受体酪氨酸激酶的内吞作用。在本研究中，我们表明，在 Fc epsilon RI 与肥大细胞系结合后，内源性 CIN85 被招募到含 Cbl 的复合物中，并驱动配体诱导的受体内化。通过共聚焦显微镜分析，我们提供的证据表明 CIN85 在早期内体中引导更快速的受体分选并递送至溶酶体区室。此外，生化研究表明CIN85在减少受体复合物的表达方面发挥作用。最后，我们证明 CIN85 过表达的肥大细胞在 Ag 刺激后脱颗粒的能力显着受损，这表明通过扰乱 Fc epsilon RI 信号的传播来加速活化受体的内化可能有助于抑制功能反应。 CIN85 的这种作用可以扩展到其他多聚体免疫受体，例如 T 细胞和 B 细胞受体，从而为减弱免疫反应提供更通用的分子机制。
Ligation of the high-affinity receptor for IgE (Fc epsilon RI), constitutively expressed on mast cells and basophils, promotes cell activation and immediate release of allergic mediators. Furthermore, Fc epsilon RI up-regulation on APC from atopic donors is involved in the pathophysiology of allergic diseases. In consideration of the clinical relevance of the IgE receptor, the down-modulation of Fc epsilon RI expression in mast cells may represent a potential target for handling atopic diseases. In an effort to identify new molecular mechanisms involved in attenuating Fc epsilon RI expression and signaling, we focused our attention on CIN85, a scaffold molecule that regulates, in concert with the ubiquitin ligase Cbl, the clathrin-mediated endocytosis of several receptor tyrosine kinases. In the present study, we show that endogenous CIN85 is recruited in Cbl-containing complexes after engagement of the Fc epsilon RI on a mast cell line and drives ligand-induced receptor internalization. By confocal microscopic analysis, we provide evidence that CIN85 directs a more rapid receptor sorting in early endosomes and delivery to a lysosomal compartment. Furthermore, biochemical studies indicate that CIN85 plays a role in reducing the expression of receptor complex. Finally, we demonstrate that CIN85-overexpressing mast cells are dramatically impaired in their ability to degranulate following Ag stimulation, suggesting that the accelerated internalization of activated receptors by perturbing the propagation of Fc epsilon RI signaling may contribute to dampen the functional response. This role of CIN85 could be extended to include other multimeric immune receptors, such as the T and B cell receptors, providing a more general molecular mechanism for attenuating immune responses.