Export of the high affinity IgE receptor from the endoplasmic reticulum depends on a glycosylation-mediated quality control mechanism

The high affinity IgE receptor (Fc epsilon RI) is a multisubunit complex comprised of either alpha gamma (2) or alpha beta gamma (2) chains. The cotranslational assembly of the IgE-binding alpha -chain with a dimer of gamma -chains occurs in a highly controlled manner and is proposed to involve masking of a dilysine motif present at the cytoplasmic C terminus of the Fc epsilon RI alpha -chain that targets localization of this subunit to the endoplasmic reticulum (ER), Here, we show that ER quality control modulates export from the ER of newly synthesized alpha gamma (2) and alpha beta gamma (2) receptors, We demonstrate that the presence of untrimmed N-linked core glycans (Gle(3)Man(9)GleNAc(2)) on the FceRI alpha -chain activates the ER quality control mechanism to retain this subunit in the ER, despite the presence of gamma -chains, At the same time, the untrimmed, ER-localized alpha -chain exhibits IgE-binding activity, suggesting that Fc epsilon RI alpha -chain folding occurs before constitutive glucose trimming. In additional experiments, we demonstrate that cell surface expression of an alpha -chain C-terminal truncation mutant is also dependent on glucose trimming, but not on gamma -chain coexpression. We suggest that glucosidase trimming of terminal glucose residues is a critical control step in the export of Fc epsilon RI alpha from the ER. Finally, we show that the constitutive ER FceRI alpha -chain, expressed in the absence of the other FceRI subunits, associates with the ER lectin-like chaperone calnexin, but not the structurally similar ER chaperone calreticulin, presumably through interaction with monoglucosylated alpha -chain ER glycoforms.