Cotranslational endoplasmic reticulum assembly of FcɛRI controls the formation of functional IgE-binding receptors

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