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The Journal of Immunology, 2005, 175: 4208-4216.
Copyright © 2005 by The American Association of Immunologists

CIN85 Regulates the Ligand-Dependent Endocytosis of the IgE Receptor: A New Molecular Mechanism to Dampen Mast Cell Function1

Rosa Molfetta*, Francesca Belleudi2,*, Giovanna Peruzzi2,*, Stefania Morrone*, Laura Leone*, Ivan Dikic{dagger}, Mario Piccoli*, Luigi Frati*, Maria Rosaria Torrisi*, Angela Santoni* and Rossella Paolini3,*

* Department of Experimental Medicine and Pathology, Institute Pasteur-Fondazione Cenci Bolognetti, University "La Sapienza," Rome, Italy; and {dagger} Institute of Biochemistry II, Goethe University Medical School, Frankfurt, Germany

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.


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