Functional relationship between protein disulfide isomerase family members during the oxidative folding of human secretory proteins

To examine the relationship between protein disulfide isomerase family members within the mammalian endoplasmic reticulum, PDI, ERp57, ERp72, and P5 were depleted with high efficiency in human hepatoma cells, either singly or in combination. The impact was assessed on the oxidative folding of severa...

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Published in:Molecular biology of the cell 2010-09, Vol.21 (18), p.3093-3105
Main Authors: Rutkevich, Lori A, Cohen-Doyle, Myrna F, Brockmeier, Ulf, Williams, David B
Format: Article
Language:English
Subjects:
Animals
Cell Line, Tumor
Gene Knockdown Techniques
Humans
Isoenzymes - genetics
Isoenzymes - metabolism
Membrane Glycoproteins - chemistry
Membrane Glycoproteins - metabolism
Nerve Tissue Proteins - chemistry
Nerve Tissue Proteins - metabolism
Oxidation-Reduction
Peptide Fragments - chemistry
Peptide Fragments - metabolism
Protein Disulfide-Isomerases - chemistry
Protein Disulfide-Isomerases - genetics
Protein Disulfide-Isomerases - metabolism
Protein Folding
RNA Interference
Unfolded Protein Response - physiology
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Summary:To examine the relationship between protein disulfide isomerase family members within the mammalian endoplasmic reticulum, PDI, ERp57, ERp72, and P5 were depleted with high efficiency in human hepatoma cells, either singly or in combination. The impact was assessed on the oxidative folding of several well-characterized secretory proteins. We show that PDI plays a predominant role in oxidative folding because its depletion delayed disulfide formation in all secretory proteins tested. However, the phenotype was surprisingly modest suggesting that other family members are able to compensate for PDI depletion, albeit with reduced efficacy. ERp57 also exhibited broad specificity, overlapping with that of PDI, but with preference for glycosylated substrates. Depletion of both PDI and ERp57 revealed that some substrates require both enzymes for optimal folding and, furthermore, led to generalized protein misfolding, impaired export from the ER, and degradation. In contrast, depletion of ERp72 or P5, either alone or in combination with PDI or ERp57 had minimal impact, revealing a narrow substrate specificity for ERp72 and no detectable role for P5 in oxidative protein folding.
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.E10-04-0356