The Journal of Experimental Medicine
ThymUS '08
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Published online 10 January 2005 doi:10.1084/jem.20041384
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 2, 267-277
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ARTICLE

 Cotranslational endoplasmic reticulum assembly of Fc{varepsilon}RI controls the formation of functional IgE-binding receptors

Edda Fiebiger1, Domenico Tortorella2, Marie-Helene Jouvin3, Jean-Pierre Kinet3, and Hidde L. Ploegh1

1 Department of Pathology, Harvard Medical School, Boston, MA 02115
2 Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029
3 Laboratory of Allergy and Immunology, Beth Israel Deaconess Medical Center, Boston, MA 02215

CORRESPONDENCE Hidde Ploegh: ploegh{at}hms.harvard.edu

The human high affinity receptor for IgE (Fc{varepsilon}RI) is a cell surface structure critical for the pathology of allergic reactions. Human Fc{varepsilon}RI is expressed as a tetramer ({alpha}ß{gamma}2) on basophils or mast cells and as trimeric ({alpha}{gamma}2) complex on antigen-presenting cells. Expression of the human {alpha} subunit can be down-regulated by a splice variant of Fc{varepsilon}RIß (ßvar). We demonstrate that Fc{varepsilon}RI{alpha} is the core subunit with which the other subunits assemble strictly cotranslationally. In addition to {alpha}ß{gamma}2 and {alpha}{gamma}2, we demonstrate the presence of {alpha}ß and {alpha}ßvar{gamma}2 complexes that are stable in the detergent Brij 96. The role of individual Fc{varepsilon}RI subunits for the formation of functional, immunoglobulin E–binding Fc{varepsilon}RI complexes during endoplasmic reticulum (ER) assembly can be defined as follows: ß and {gamma} support ER insertion, signal peptide cleavage and proper N-glycosylation of {alpha}, whereas ßvar allows accumulation of {alpha} protein backbone. We show that assembly of Fc{varepsilon}RI in the ER is a key step for the regulation of surface expression of Fc{varepsilon}RI. The ER quality control system thus regulates the quantity of functional Fc{varepsilon}RI, which in turn controls onset and persistence of allergic reactions.

Abbreviations used: CC, U373; EndoH, endoglycosidase H; ITAM, immunoreceptor tyrosine–based signaling motifs.


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