The Erv41–Erv46 complex serves as a retrograde receptor to retrieve misfolded secretory proteins that have escaped from the ER

The Erv41-Erv46 complex is a conserved transmembrane cargo receptor that returns endoplasmic reticulum (ER)-resident proteins that have reached the Golgi complex back to the ER. Here, we report that this retrograde receptor also retrieves misfolded secretory cargo that contain luminal domain lesions, such as CPY*. Cells lacking Erv41-Erv46, increase the cellular clearance of misfolded cargo proteins due to increased ER escape and transport to the cell surface or to the vacuole for degradation. Erv41-Erv46 displays selectivity in binding misfolded substrates compared with their folded counterparts. Binding experiments reconstituted with purified proteins demonstrate that Erv41-Erv46 complex binds directly to misfolded CPY* through a shared cargo-binding site. These findings indicate that Erv41-Erv46 acts as a post-ER protein quality control checkpoint and expand the client range by which retrograde receptors ensure delivery of correctly folded secretory proteins.