The K/HDEL receptor does not recycle, but instead acts as a Golgi-gatekeeper

Abstract The K/HDEL receptor (ER retention defective 2 or ERD2) does not recycle between compartments when sorting ER chaperones, contrary to the favoured model. A conserved C-terminal di-leucine motif specifically prevents ERD2 Golgi-to-ER transport and is not required for ER export. The Golgi-retention mechanism strips Golgi-membranes of the GTPase ARF1 so that ERD2 avoids accompanying its ligands in retrograde transport. When this motif is deleted or masked, introducing a fast ER-to-Golgi export signal or an alternative cis-Golgi retention signal re-activates ERD2. Meanwhile, forcing retrograde transport renders the receptor non-functional. We have established an in vivo ligand/receptor ratio far greater than 100 to 1, and propose a gatekeeper model to explain how few receptors at the Golgi can prevent the secretion of highly abundant soluble ER proteins. The underlying mechanism is conserved across kingdoms and will yield valuable insight into Golgi-mediated cargo sorting and cisternal compartment maintenance.