Evidence that luminal ER proteins are sorted from secreted proteins in a post-ER compartment.

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Abstract
Several soluble proteins that reside in the lumen of the ER contain a specific C‐terminal sequence (KDEL) which prevents their secretion. This sequence may be recognized by a receptor that either immobilizes the proteins in the ER, or sorts them from other proteins at a later point in the secretory pathway and returns them to their normal location. To distinguish these possibilities, I have attached an ER retention signal to the lysosomal protein cathepsin D. The oligosaccharide side chains of this protein are normally modified sequentially by two enzymes to form mannose‐6‐phosphate residues; these enzymes do not act in the ER, but are thought to be located in separate compartments within (or near) the Golgi apparatus. Cathepsin D bearing the ER signal accumulates within the ER, but continues to be modified by the first of the mannose‐6‐phosphate forming enzymes. Modification is strongly temperature‐dependent, which is also a feature of ER‐to‐Golgi transport. These results support the idea that luminal ER proteins are continuously retrieved from a post‐ER compartment, and that this compartment contains N‐acetylglucosaminyl‐1‐phosphotransferase activity.