The pivotal role of ERp44 in patrolling protein secretion

Interactions between protein ligands and receptors are the main language of intercellular communication; hence, how cells select proteins to be secreted or presented on the plasma membrane is a central concern in cell biology. A series of checkpoints are located along the secretory pathway, which ensure the fidelity of such protein signals (quality control). Proteins that pass the checkpoints operated in the endoplasmic reticulum (ER) by the binding immunoglobulin protein (BiP; also known as HSPA5 and GRP78) and the calnexin–calreticulin systems, must still overcome additional scrutiny in the ER-Golgi intermediate compartment (ERGIC) and the Golgi. One of the main players of this process in all metazoans is the ER-resident protein 44 (ERp44); by cycling between the ER and the Golgi, ERp44 controls the localization of key enzymes designed to act in the ER but that are devoid of suitable localization motifs. ERp44 also patrols the secretion of correctly assembled disulfide-linked oligomeric proteins. Here, we discuss the mechanisms driving ERp44 substrate recognition, with important consequences on the definition of ‘thiol-mediated quality control’. We also describe how pH and zinc gradients regulate the functional cycle of ERp44, coupling quality control and membrane trafficking along the early secretory compartment.