MUTANT ANALYSIS LINKS THE TRANSLOCON AND BIP TO RETROGRADE PROTEIN-TRANSPORT FOR ER DEGRADATION

Proteins enter the secretory pathway through the endoplasmic reticulum (1), which delivers properly folded proteins to their site of action(2 ) and contains a quality-control system to monitor and prevent abnorma l proteins from being delivered(3), Many of these proteins are degrade d by the cytoplasmic proteasome(4-8), which requires their retrograde transport to the cytoplasm(5,6). Based on a co-immunoprecipitation of major histocompatibility complex (MHC) class I heavy-chain breakdown i ntermediates with the translocon subunit Sec61p (refs 9, 10), it was s peculated that Sec61p maybe involved in retrograde transport(11), Here we present functional evidence from genetic studies that Sec61p media tes retrograde transport of a mutated lumenal yeast carboxypeptidase y csY (CPY) in vivo. The endoplasmic reticulum lumenal chaperone BiP (K ar2p) and Sec63p, which are also subunits of the import machinery(10,1 2), are involved in export of CPY to the cytosol, Thus our results de monstrate that retrograde transport of proteins is mediated by a funct ional translocon. We consider the export of endoplasmic reticulum-loca lized proteins to the cytosol by the translocon for proteasome degrada tion to be a general process in eukaryotic cell biology.