CIN85 regulates the ligand-dependent endocytosis of the IgE receptor: a new molecular mechanism to dampen mast cell function.
Ligation of the high-affinity receptor for IgE (Fc epsilonRI), constitutively expressed on mast cells and basophils, promotes cell activation and immediate release of allergic mediators. Furthermore, Fc epsilonRI 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 epsilonRI 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 epsilonRI 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 epsilonRI 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 epsilonRI 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.
Molfetta
Rosa
R
Department of Experimental Medicine and Pathology, Institute Pasteur-Fondazione Cenci Bolognetti, University La Sapienza, Rome, Italy.
Belleudi
Francesca
F
Peruzzi
Giovanna
G
Morrone
Stefania
S
Leone
Laura
L
Dikic
Ivan
I
Piccoli
Mario
M
Frati
Luigi
L
Torrisi
Maria Rosaria
MR
Santoni
Angela
A
Paolini
Rossella
R
D000818:Animals; D015550:Cell Degranulation / Q000502:physiology; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000502:physiology; D004705:Endocytosis / Q000276:immunology*; D011992:Endosomes / Q000378:metabolism; D008024:Ligands; D008247:Lysosomes / Q000378:metabolism; D008407:Mast Cells / Q000276:immunology* / Q000473:pathology; D009363:Neoplasm Proteins / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D051381:Rats; D017455:Receptors, IgE / Q000235:genetics / Q000378:metabolism*
D008024:Ligands; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D017455:Receptors, IgE; C411889:Sh3kbp1 protein, rat