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

• Greg J Poet ^[2] ; Ojore BV Oka ^[1] ; Marcel van Lith ^[1] ; Zhenbo Cao ^[1] ; Philip J Robinson ^[1] ; Marie Anne Pringle ^[1] ; Elias SJ Arnér ^[3] ; Neil J Bulleid ^[1]
  1. [1] University of Glasgow

     University of Glasgow

     Reino Unido

     
  2. [2] 1 The Institute of Molecular, Cell and Systems Biology CMVLS University of Glasgow Glasgow UK; Present address: St. Jude Children's Research HospitalMemphisTNUSA
  3. [3] 2 Division of Biochemistry Department of Medical Biochemistry and Biophysics (MBB) Karolinska Institutet Stockholm Sweden

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 36, Nº. 5, 2017, págs. 693-702
• Idioma: inglés
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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.