Export of transmembrane proteins from the endoplasmic reticulum (ER) is driven by directed incorporation into coat protein complex II (COPII)-coated vesicles. The sorting of some cargo proteins into COPII vesicles was shown to be mediated by specific interactions between transmembrane and COPII-coat-forming proteins. But even though some signals for ER exit have been identified on the cytosolic domains of membrane proteins, the general signaling and sorting mechanisms of ER export are still poorly understood. To investigate the role of cargo protein oligomer formation in the export process, we have created a transmembrane fusion protein that – owing to its FK506-binding protein domains – can be oligomerized in isolated membranes by addition of a small-molecule dimerizer. Packaging of the fusion protein into COPII vesicles is strongly enhanced in the presence of the dimerizer, demonstrating that the oligomeric state is an ER export signal for this membrane protein. Surprisingly, the cytosolic tail is not required for this oligomerization-dependent effect on protein sorting. Thus, an alternative mechanism, such as membrane bending, must account for ER export of the fusion protein.
In this study, induced oligomerization of a model transmembrane cargo protein stimulates its ER export in vitro independent of known export signals. Sec24-binding motifs in the cytosolic tail of the protein are not required for incorporation into COPII transport vesicles generated in vitro and instead the efficiency of ER exit is strongly dependent on the degree of oligomerization. We propose that oligomerization of this transmembrane protein induces local membrane bending, which in turn promotes COPII vesicle generation.