A pH-Regulated Quality Control Cycle for Surveillance of Secretory Protein Assembly

Summary To warrant the quality of the secretory proteome, stringent control systems operate at the endoplasmic reticulum (ER)-Golgi interface, preventing the release of nonnative products. Incompletely assembled oligomeric proteins that are deemed correctly folded must rely on additional quality control mechanisms dedicated to proper assembly. Here we unveil how ERp44 cycles between cisGolgi and ER in a pH-regulated manner, patrolling assembly of disulfide-linked oligomers such as IgM and adiponectin. At neutral, ER-equivalent pH, the ERp44 carboxy-terminal tail occludes the substrate-binding site. At the lower pH of the cisGolgi, conformational rearrangements of this peptide, likely involving protonation of ERp44’s active cysteine, simultaneously unmask the substrate binding site and −RDEL motif, allowing capture of orphan secretory protein subunits and ER retrieval via KDEL receptors. The ERp44 assembly control cycle couples secretion fidelity and efficiency downstream of the calnexin/calreticulin and BiP-dependent quality control cycles.
Graphical Abstract
Highlights • ERp44 governs a pH-regulated assembly control cycle in the early secretory pathway • Accessibility of ERp44’s active site and –RDEL ER retrieval motif is pH dependent • Unmasking of ERp44’s active site likely involves protonation of cysteine 29 • ERp44 captures client proteins at cisGolgi-equivalent pH for retrieval to the ER