ERp18 regulates the activation of ATF6α during the unfolded protein response

Oka, O. B.V. , van Lith, M., Rudolf, J., Tungkum, W., Pringle, M.-A. and Bulleid, N. J. (2019) ERp18 regulates the activation of ATF6α during the unfolded protein response. EMBO Journal, 2019, e100990. (doi:10.15252/embj.2018100990) (PMID:31209066)

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Abstract

Activation of the ATF6α signaling pathway is initiated by trafficking of ATF6α from the ER to the Golgi apparatus. Its subsequent proteolysis releases a transcription factor that translocates to the nucleus causing downstream gene activation. How ER retention, Golgi trafficking, and proteolysis of ATF6α are regulated and whether additional protein partners are required for its localization and processing remain unresolved. Here, we show that ER‐resident oxidoreductase ERp18 associates with ATF6α following ER stress and plays a key role in both trafficking and activation of ATF6α. We find that ERp18 depletion attenuates the ATF6α stress response. Paradoxically, ER stress accelerates trafficking of ATF6α to the Golgi in ERp18‐depleted cells. However, the translocated ATF6α becomes aberrantly processed preventing release of the soluble transcription factor. Hence, we demonstrate that ERp18 monitors ATF6α ER quality control to ensure optimal processing following trafficking to the Golgi.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Bulleid, Professor Neil and Tungkum, Wanida and Van Lith, Dr Marcel and Rudolf, Dr Jana and Oka, Dr Ojore and Pringle, Mrs Marie
Authors: Oka, O. B.V., van Lith, M., Rudolf, J., Tungkum, W., Pringle, M.-A., and Bulleid, N. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:EMBO Journal
Publisher:EMBO Press
ISSN:0261-4189
ISSN (Online):1460-2075
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in EMBO Journal 2019:e100990
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
652801Protein Folding and Thiol Modification in the Mammalian Endoplasmic ReticulumNeil BulleidWellcome Trust (WELLCOTR)103720/Z/14/ZRI MOLECULAR CELL & SYSTEMS BIOLOGY
632234Funding SchemesAnna DominiczakWellcome Trust (WELLCOTR)105614/Z/14/ZRI CARDIOVASCULAR & MEDICAL SCIENCES