Degradation of endoplasmic reticulum (ER) quality control substrates requires transport between the ER and Golgi

Endoplasmic reticulum (ER) quality control (ERQC) components retain and deg rade misfolded proteins, and our results have found that the degradation of the soluble ERQC substrates CPY* and PrA* but not membrane spanning ERQC s ubstrates requires transport between the ER and Golgi. Stabilization of the se misfolded soluble proteins was seen in cells lacking Erv29p, a probable Golgi localized protein that cycles through the ER by means of a di-lysine ER retrieval motif (KKKIY). Cells lacking Erv29p also displayed severely re tarded ER exit kinetics for a subset of correctly folded proteins. We sugge st that Erv29p is likely involved in cargo loading of a subset of proteins, including soluble misfolded proteins, into vesicles for ER exit. The stabi lization of soluble ERQC substrates in both erv29 Delta cells and sec mutan ts blocked in either ER exit (sec12) or vesicle delivery to the Golgi (sec1 8) suggests that ER-Golgi transport is required for ERQC and reveals a new aspect of the degradative mechanism.