Activation of the UPR sensor ATF6α is regulated by its redox-dependent dimerization and ER retention by ERp18

Oka, O. B. V. , Pierre, A. S., Pringle, M. A. , Tungkum, W., Cao, Z., Fleming, B. and Bulleid, N. J. (2022) Activation of the UPR sensor ATF6α is regulated by its redox-dependent dimerization and ER retention by ERp18. Proceedings of the National Academy of Sciences of the United States of America, 119(12), e2122657119. (doi: 10.1073/pnas.2122657119) (PMID:35286189) (PMCID:PMC8944254)

Abstract

The unfolded protein response (UPR) maintains cellular proteostasis during stress by activating sensors located to the endoplasmic reticulum (ER) membrane. A major sensor for this response, ATF6α, is activated by release from ER retention and trafficking to the Golgi, where it is cleaved to generate a bZIP transactivator to initiate a transcriptional response. The reduction of a disulfide in monomeric ATF6α is thought to be necessary for release from retention, trafficking, and proteolysis. Here we show that, following ER stress, ATF6α undergoes a redox switch to form a disulfide bonded dimer, which traffics to the Golgi for cleavage by the S1P protease. Additionally, we find that overexpression of ERp18 attenuates dimer formation thereby limiting Golgi trafficking. Our results provide mechanistic insight into activation of the ATF6α pathway, revealing an unexpected role for redox-dependent oligomerization prior to Golgi trafficking.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cao, Dr Zhenbo and Fleming, Miss Bethany and Bulleid, Professor Neil and Pierre, Arvin and Oka, Dr Ojore and Pringle, Mrs Marie and Tungkum, Wanida
• Authors: Oka, O. B. V., Pierre, A. S., Pringle, M. A., Tungkum, W., Cao, Z., Fleming, B., and Bulleid, N. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Proceedings of the National Academy of Sciences of the United States of America
• Publisher: National Academy of Sciences
• ISSN: 0027-8424
• ISSN (Online): 1091-6490
• Published Online: 14 March 2022
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in Proceedings of the National Academy of Sciences of the United States of America 119(12): e2122657119
• 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
174173		How does the cytosol reduce non-native disulfides formed in the endoplasmic reticulum?	Neil Bulleid	Biotechnology and Biological Sciences Research Council (BBSRC)	BB/P017665/1	Institute of Molecular, Cell & Systems Biology