Cao, X., Lilla, S., Cao, Z., Pringle, M. A., Oka, O. B.V. , Robinson, P. J. , Szmaja, T., Van Lith, M., Zanivan, S. and Bulleid, N. (2020) The mammalian cytosolic thioredoxin reductase pathway acts via a membrane 1 protein to reduce ER-localised proteins. Journal of Cell Science, 133, jcs241976. (doi: 10.1242/jcs.241976) (PMID:32184267) (PMCID:PMC7197872)
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Abstract
Folding of proteins entering the mammalian secretory pathway requires the insertion of the correct disulfides. Disulfide formation involves both an oxidative pathway for their insertion and a reductive pathway to remove incorrectly formed disulfides. Reduction of these disulfides is critical for correct folding and degradation of misfolded proteins. Previously, we showed that the reductive pathway is driven by NADPH generated in the cytosol. Here, by reconstituting the pathway using purified proteins and ER microsomal membranes, we demonstrate that the thioredoxin reductase system provides the minimal cytosolic components required for reducing proteins within the ER lumen. In particular, saturation of the pathway and its protease sensitivity demonstrates the requirement for a membrane protein to shuttle electrons from the cytosol to the ER. These results provide compelling evidence for the critical role of the cytosol in regulating ER redox homeostasis ensuring correct protein folding and facilitating the degradation of misfolded ER proteins.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Van Lith, Dr Marcel and Cao, Dr Zhenbo and Bulleid, Professor Neil and Lilla, Dr Sergio and Szmaja, Tomasz and Zanivan, Professor Sara and Cao, Xiaofei and Robinson, Dr Philip and Oka, Dr Ojore |
| Authors: | Cao, X., Lilla, S., Cao, Z., Pringle, M. A., Oka, O. B.V., Robinson, P. J., Szmaja, T., Van Lith, M., Zanivan, S., and Bulleid, N. |
| College/School: | College of Medical Veterinary and Life Sciences College of Medical Veterinary and Life Sciences > School of Cancer Sciences College of Medical Veterinary and Life Sciences > School of Molecular Biosciences |
| Journal Name: | Journal of Cell Science |
| Publisher: | Company of Biologists |
| ISSN: | 0021-9533 |
| ISSN (Online): | 1477-9137 |
| Published Online: | 17 March 2020 |
| Copyright Holders: | Copyright © 2020 The Company of Biologists Ltd |
| First Published: | First published in Journal of Cell Science 133:jcs241976 |
| Publisher Policy: | Published under a Creative Commons License |
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