Distinct role of ERp57 and ERdj5 as a disulfide isomerase and reductase during ER protein folding

Robinson, P. J. , Pringle, M. A. , Fleming, B. and Bulleid, N. J. (2023) Distinct role of ERp57 and ERdj5 as a disulfide isomerase and reductase during ER protein folding. Journal of Cell Science, 136(2), jcs260656. (doi: 10.1242/jcs.260656) (PMID:36655611) (PMCID:PMC10022741)

Abstract

Proteins entering the secretory pathway need to attain native disulfide pairings to fold correctly. For proteins with complex disulfides, this process requires the reduction and isomerisation of non-native disulfides. Two key members of the protein disulfide isomerase (PDI) family, ERp57 and ERdj5 (also known as PDIA3 and DNAJC10, respectively), are thought to be required for correct disulfide formation but it is unknown whether they act as a reductase, an isomerase or both. In addition, it is unclear how reducing equivalents are channelled through PDI family members to substrate proteins. Here, we show that neither enzyme is required for disulfide formation, but ERp57 is required for isomerisation of non-native disulfides within glycoproteins. In addition, alternative PDIs compensate for the absence of ERp57 to isomerise glycoprotein disulfides, but only in the presence of a robust reductive pathway. ERdj5 is required for this alternative pathway to function efficiently indicating its role as a reductase. Our results define the essential cellular functions of two PDIs, highlighting a distinction between formation, reduction and isomerisation of disulfide bonds.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Bulleid, Professor Neil and Fleming, Miss Bethany and Pringle, Mrs Marie and Robinson, Dr Philip
• Authors: Robinson, P. J., Pringle, M. A., Fleming, B., and Bulleid, N. J.
• College/School: 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: 19 January 2023
• Copyright Holders: Copyright © 2023 The Company of Biologists Ltd
• First Published: First published in Journal of Cell Science 136(2): jcs260656
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
190840		Protein Folding and Thiol Modification in the Mammalian Endoplasmic Reticulum	Neil Bulleid	Wellcome Trust (WELLCOTR)	103720/Z/14/Z	Institute of Molecular, Cell & Systems Biology