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© The Rockefeller University Press, 0021-9525/1999/12/1443/ $5.00
The Journal of Cell Biology, Volume 147, Number 7, December 27, 1999 1443-1456

Original Article

Export of a Cysteine-free Misfolded Secretory Protein from the Endoplasmic Reticulum for Degradation Requires Interaction with Protein Disulfide Isomerase

Pauline Gillecea, José Manuel Luzc, William J. Lennarzc, Francisco Javier de la Cruzb, and Karin Römischa
a University of Cambridge, Cambridge Institute for Medical Research, Wellcome Center for the Study of Molecular Mechanisms in Disease, Cambridge CB2 2XY, United Kingdom
b Department of Biochemistry, University College London, London WC1E 6BT, United Kingdom
c Department of Biochemistry and Cell Biology, State University of New York, Stony Brook, New York 11794-5215

Correspondence to: Karin Römisch, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Center for the Study of Molecular Mechanisms in Disease, Hills Road, Cambridge CB2 2XY, UK. Tel:+44-1223-762 638 Fax:+44-1223-762 640 E-mail:kbr20{at}cam.ac.uk.

Protein disulfide isomerase (PDI) interacts with secretory proteins, irrespective 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 molecule to investigate its role in the recognition of misfolded secretory proteins 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, but ER-to-Golgi complex transport of properly folded secretory proteins is only marginally affected. We demonstrate by chemical cross-linking that PDI specifically 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 associated with BiP, and in export-deficient sec61 mutants, the misfolded secretory protein remain bounds to PDI. We conclude that the chaperone PDI is part of the quality control machinery in the ER that recognizes terminally misfolded secretory proteins and targets them to the export channel in the ER membrane.

Key Words: protein disulfide isomerase, endoplasmic reticulum-associated degradation, endoplasmic reticulum quality control, BiP, yeast


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