The Signal Peptide of the IgE Receptor α-Chain Prevents Surface Expression of an Immunoreceptor Tyrosine-based Activation Motif-free Receptor Pool

The high affinity receptor for IgE, Fc epsilon receptor I (Fc epsilon RI), is an activating immune receptor and key regulator of allergy. Antigen-mediated cross-linking of IgE-loaded Fc epsilon RI alpha-chains induces cell activation via immunoreceptor tyrosine-based activation motifs in associated signaling subunits, such as Fc epsilon RI gamma-chains. Here we show that the human Fc epsilon RI alpha-chain can efficiently reach the cell surface by itself as an IgE-binding receptor in the absence of associated signaling subunits when the endogenous signal peptide is swapped for that of murine major histocompatibility complex class-I H2-K-b. This single-chain isoform of Fc epsilon RI exited the endoplasmic reticulum (ER), trafficked to the Golgi and, subsequently, trafficked to the cell surface. Mutational analysis showed that the signal peptide regulates surface expression in concert with other described ER retention signals of Fc epsilon RI-alpha. Once the Fc epsilon RI alpha-chain reached the cell surface by itself, it formed a ligand-binding receptor that stabilized upon IgE contact. Independently of the Fc epsilon RI gamma-chain, this single-chain Fc epsilon RI was internalized after receptor cross-linking and trafficked into a LAMP-1-positive lysosomal compartment like multimeric Fc epsilon RI. These data suggest that the single-chain isoform is capable of shuttling IgE-antigen complexes into antigen loading compartments, which plays an important physiologic role in the initiation of immune responses toward allergens. We propose that, in addition to cytosolic and transmembrane ER retention signals, the Fc epsilon RI alpha-chain signal peptide contains a negative regulatory signal that prevents expression of an immunoreceptor tyrosine-based activation motif-free IgE receptor pool, which would fail to induce cell activation.