Cytosolic thioredoxin reductase 1 is required for correct disulfide formation in the ER

Poet, G. J., Oka, O. B.V. , Van Lith, M., Cao, Z., Robinson, P. J. , Pringle, M. A. , Arnér, E. S.J. and Bulleid, N. (2017) Cytosolic thioredoxin reductase 1 is required for correct disulfide formation in the ER. EMBO Journal, 36(5), pp. 693-702. (doi: 10.15252/embj.201695336) (PMID:28093500) (PMCID:PMC5331760)

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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 TXNRD1). 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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Van Lith, Dr Marcel and Cao, Dr Zhenbo and Bulleid, Professor Neil and Pringle, Mrs Marie and Robinson, Dr Philip and Oka, Dr Ojore
Authors: Poet, G. J., Oka, O. B.V., Van Lith, M., Cao, Z., Robinson, P. J., Pringle, M. A., Arnér, E. S.J., and Bulleid, N.
College/School:College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:EMBO Journal
Publisher:EMBO Press
ISSN (Online):1460-2075
Published Online:16 January 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in EMBO Journal 36(5):693-702
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
652801Protein Folding and Thiol Modification in the Mammalian Endoplasmic ReticulumNeil BulleidWellcome Trust (WELLCOME)103720/Z/14/ZRI MOLECULAR CELL & SYSTEMS BIOLOGY
638691Identifying the reductive pathway in the mammalian endoplasmic reticulum.Neil BulleidBiotechnology and Biological Sciences Research Council (BBSRC)BB/L00593X/1RI MOLECULAR CELL & SYSTEMS BIOLOGY
500151Doctoral Training Grant 2009-15Timothy PalmerBiotechnology and Biological Sciences Research Council (BBSRC)BB/F016735/1RI CARDIOVASCULAR & MEDICAL SCIENCES