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Cytosolic thioredoxin reductase 1 is required for correct disulfide formation in the ER
Author(s) -
Poet Greg J,
Oka Ojore BV,
Lith Marcel,
Cao Zhenbo,
Robinson Philip J,
Pringle Marie Anne,
Arnér Elias SJ,
Bulleid Neil J
Publication year - 2017
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201695336
Subject(s) - biology , cytosol , ferredoxin thioredoxin reductase , thioredoxin reductase , thioredoxin , biochemistry , disulfide bond , reductase , enzyme , microbiology and biotechnology
Folding of proteins entering the secretory pathway in mammalian cells frequently requires the insertion of disulfide bonds. Disulfide insertion can result in covalent linkages found in the native structure as well as those that are not, so‐called non‐native disulfides. The pathways for disulfide formation are well characterized, but our understanding of how non‐native disulfides are reduced so that the correct or native disulfides can form is poor. Here, we use a novel assay to demonstrate that the reduction in non‐native disulfides requires NADPH as the ultimate electron donor, and a robust cytosolic thioredoxin system, driven by thioredoxin reductase 1 (TrxR1 or TXNRD 1). Inhibition of this reductive pathway prevents the correct folding and secretion of proteins that are known to form non‐native disulfides during their folding. Hence, we have shown for the first time that mammalian cells have a pathway for transferring reducing equivalents from the cytosol to the ER , which is required to ensure correct disulfide formation in proteins entering the secretory pathway.