Export of a cysteine-free misfolded secretory protein from the endoplasmicreticulum for degradation requires interaction with protein disulfide isomerase

Protein disulfide isomerase (PDI) interacts with secretory proteins, irresp ective of their thiol content, late during translocation into the ER; thus, PDI may be part of the quality control machinery in the ER. We used yeast pdi1 mutants with deletions in the putative peptide binding region of the m olecule to investigate its role in the recognition of misfolded secretory p roteins in the ER and their export to the cytosol for degradation. Our pdi1 deletion mutants are deficient in the export of a misfolded cysteine-free secretory protein across the ER membrane to the cytosol for degradation, bu t ER-to-Golgi complex transport of properly folded secretory proteins is on ly marginally affected. We demonstrate by chemical cross-linking that PDI s pecifically interacts with the misfolded secretory protein and that mutant forms of PDI have a lower affinity for this protein. In the ER of the pdi1 mutants, a higher proportion of the misfolded secretory protein remains ass ociated with BiP, and in export-deficient sec61 mutants, the misfolded secr etory protein remain bounds to PDI. We conclude that the chaperone PDI is p art of the quality control machinery in the ER that recognizes terminally m isfolded secretory proteins and targets them to the export channel in the E R membrane.