1. Institut für Biochemie der Universität Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany
2. Max-Delbrück-Centrum für Molekulare Medizin, Robert-Rössle Strasse 10, D-13122 Berlin, Germany

Correspondence to: Correspondence and requests for materials should be addressed to D.H.W. (e-mail: Email: dieter.wolf@po.uni-stuttgart.de).

Proteins enter the secretory pathway through the endoplasmic reticulum¹, which delivers properly folded proteins to their site of action² and contains a quality-control system to monitor and prevent abnormal proteins from being delivered³. Many of these proteins are degraded by the cytoplasmic proteasome^{4, 5, 6, 7, 8}, which requires their retrograde transport to the cytoplasm⁵,⁶. Based on a co-immunoprecipitation of major histocompatibility complex (MHC) class I heavy-chain breakdown intermediates with the translocon subunit Sec61p (refs 9, 10), it was speculated that Sec61p may be involved in retrograde transport¹¹. Here we present functional evidence from genetic studies that Sec61p mediates retrograde transport of a mutated lumenal yeast carboxypeptidase ycsY (CPY*) in vivo. The endoplasmic reticulum lumenal chaperone BiP (Kar2p) and Sec63p, which are also subunits of the import machinery¹⁰,¹², are involved in export of CPY* to the cytosol. Thus our results demonstrate that retrograde transport of proteins is mediated by a functional translocon. We consider the export of endoplasmic reticulum-localized proteins to the cytosol by the translocon for proteasome degradation to be a general process in eukaryotic cell biology.