Erythropoietin controls surface expression of its receptor via endoplasmic reticulum translocation.

Approximately one third of all newly synthesized proteins are estimated to be processed through the secretory pathway. This complex process presents multiple opportunities for regulation of protein production and function. Current examples of the differential regulation of translocation of specific polypeptides across the Endoplasmic Reticulum (ER) membrane, have focused on the responses to ER stress. Differences in the folding surrounding between the cytosol and the ER lumen, prevent mislocalized proteins from properly folding thus making them highly toxic to the cell. As such, mislocalized proteins are subjected to proteasomal degradation by the pre-emptive quality control (pQC) process which is viewed as part of the unfolded protein response (UPR). Accumulatively, the various UPR cellular process aim to maintain ER homeostasis during changes in physiological or stress conditions. Here we used a specific ER translocation inhibitor, CAM741 (Novartis), to demonstrate that the regulated translocation of the erythropoietin receptor (EPOR) into the ER lumen responds to erythropoietin hormone levels. Our results suggest a new mode of regulation by which extra-cellular signaling can affect the entry of specific nascent chains into the ER lumen. Uncovering the mechanism by which extra-cellular conditions regulate ER translocation of a specific polypeptide has potential as a means of intervention, with potential clinical implications.