University of Oulu

Moilanen, A., Ruddock, L. W. (2020). Non-native proteins inhibit the ER oxidoreductin 1 (Ero1)–protein disulfide-isomerase relay when protein folding capacity is exceeded. Journal of Biological Chemistry, 295(26), 8647-8655,. http://doi.org/10.1074/jbc.RA119.011766

Non-native proteins inhibit the ER oxidoreductin 1 (Ero1)–protein disulfide-isomerase relay when protein folding capacity is exceeded

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Author: Moilanen, Antti1; Ruddock, Lloyd W.1
Organizations: 1Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90220 Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.6 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2020090868880
Language: English
Published: American Society for Biochemistry and Molecular Biology, 2020
Publish Date: 2020-09-08
Description:

Abstract

Protein maturation in the endoplasmic reticulum (ER) depends on a fine balance between oxidative protein folding and quality control mechanisms, which together ensure high-capacity export of properly folded proteins from the ER. Oxidative protein folding needs to be regulated to avoid hyperoxidation. The folding capacity of the ER is regulated by the unfolded protein response (UPR) and ER-associated degradation (ERAD). The UPR is triggered by unfolded protein stress and leads to up-regulation of cellular components such as chaperones and folding catalysts. These components relieve stress by increasing folding capacity and up-regulating ERAD components that remove non-native proteins. Although oxidative protein folding and the UPR/ERAD pathways each are well-understood, very little is known about any direct cross-talk between them. In this study, we carried out comprehensive in vitro activity and binding assays, indicating that the oxidative protein folding relay formed by ER oxidoreductin 1 (Ero1), and protein disulfide-isomerase can be inactivated by a feedback inhibition mechanism involving unfolded proteins and folding intermediates when their levels exceed the folding capacity of the system. This mechanism allows client proteins to remain mainly in the reduced state and thereby minimizes potential futile oxidation–reduction cycles and may also enhance ERAD, which requires reduced protein substrates. Relief from excess levels of non-native proteins by increasing the levels of folding factors removed the feedback inhibition. These results reveal regulatory cross-talk between the oxidative protein folding and UPR and ERAD pathways.

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Series: Journal of biological chemistry
ISSN: 0021-9258
ISSN-E: 1083-351X
ISSN-L: 0021-9258
Volume: 295
Issue: 26
Pages: 8647 - 8655
DOI: 10.1074/jbc.RA119.011766
OADOI: https://oadoi.org/10.1074/jbc.RA119.011766
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Subjects:
Funding: This work was supported by Academy of Finland Grant 272573 and by Biocenter Oulu. A patent for the production system used to make the protein for structural studies using sulfhydryl oxidases in the cytoplasm of E. coli is held by the University of Oulu: Method for producing natively folded proteins in a prokaryotic host (Patent 9238817, January 19, 2016, inventor L. W. Ruddock).
Academy of Finland Grant Number: 272573
Detailed Information: 272573 (Academy of Finland Funding decision)
Copyright information: © 2020 Moilanen and Ruddock. Published by The American Society for Biochemistry and Molecular Biology, Inc. Author’s Choice—Final version open access under the terms of the Creative Commons CC-BY license
  https://creativecommons.org/licenses/by/4.0/