The distinction between proteins exported from and those retained in the ER appears to be governed by two distinct types of targeting sequences that specifically mark proteins as either (1) destined for transport to the Golgi or (2) destined for retention in the ER. Many proteins are retained in the ER lumen as a result of the presence of the targeting sequence Lys-Asp-Glu-Leu (KDEL, in the single-letter code) at their carboxy terminus. If this sequence is deleted from a protein that is normally retained in the ER (e.g., BiP), the mutated protein is instead transported to the Golgi and secreted from the cell. Conversely, addition of the KDEL sequence to the carboxy terminus of proteins that are normally secreted causes them to be retained in the ER. The retention of some transmembrane proteins in the ER is similarly dictated by short C-terminal sequences that contain two lysine residues (KKXX sequences).
Interestingly, the KDEL and KKXX signals do not prevent soluble ER proteins from being packaged into vesicles and carried to the Golgi. Instead, these signals cause resident ER proteins to be selectively retrieved from the ER-Golgi intermediate compartment or the Golgi complex and returned to the ER via a recycling pathway (Figure 9.21).
Figure 9.21. Retrieval of resident ER proteins Proteins destined to remain in the lumen of the ER are marked by the sequence Lys-Asp-Glu-Leu (KDEL) at their carboxy terminus. These proteins are exported from the ER to the Golgi in the nonselective bulk flow of proteins through the secretory pathway, but they are recognized by a receptor in the ER-Golgi intermediate compartment (ERGIC) or the Golgi apparatus and selectively returned to the ER.
Proteins bearing the KDEL and KKXX sequences appear to bind to specific recycling receptors in the membranes of these compartments and are then selectively transported back to the ER.
The action of the KDEL and KKXX sequences as retention/retrieval signals indicates that there is a nonselective bulk flow of proteins through the secretory pathway leading from the ER to the cell surface. This bulk flow from the ER to the Golgi may be responsible for the export of many proteins from the ER. However, it also appears that some proteins destined for secretion are marked by signals that actively direct their export from the ER. Protein export from the ER can thus take place not only by bulk flow, but also by a regulated pathway that specifically recognizes targeting signals that mediate selective transport of proteins to the Golgi apparatus