The K/HDEL receptor does not recycle but instead acts as a Golgi-gatekeeper

Alvim, J. C. et al. (2023) The K/HDEL receptor does not recycle but instead acts as a Golgi-gatekeeper. Nature Communications, 14, 1612. (doi: 10.1038/s41467-023-37056-0) (PMID:36959220) (PMCID:PMC10036638)

Abstract

Accurately measuring the ability of the K/HDEL receptor (ERD2) to retain the ER cargo Amy-HDEL has questioned earlier results on which the popular receptor recycling model is based upon. Here we demonstrate that ERD2 Golgi-retention, rather than fast ER export supports its function. Ligand-induced ERD2 redistribution is only observed when the C-terminus is masked or mutated, compromising the signal that prevents Golgi-to-ER transport of the receptor. Forcing COPI mediated retrograde transport destroys receptor function, but introducing ER-to-Golgi export or cis-Golgi retention signals re-activate ERD2 when its endogenous Golgi-retention signal is masked or deleted. We propose that ERD2 remains fixed as a Golgi gatekeeper, capturing K/HDEL proteins when they arrive and releasing them again into a subdomain for retrograde transport back to the ER. An in vivo ligand:receptor ratio far greater than 100 to 1 strongly supports this model, and the underlying mechanism appears to be extremely conserved across kingdoms.

• Item Type: Articles
• Additional Information: The work in this article was in part supported by the European Union (projects HPRN-CT-2002-00262 and LSH-2002-1.2.5-2), the Biotechnology and Biological Sciences Research Council (BBSRC) project nr. BB/D016223/1, The Leverhulme Trust (F/10 105/E) and the São Paulo Research Foundation (FAPESP), Brazil (grant no.: 19/02418-9 and 19/26119-0). Jonas C. Alvim is grateful for a PhD scholarship awarded from the Conselho Nacional de Desenvolvimento Científico e Tecnológico – Brasil (CNPq 201192/2014-4). Robert M. Bolt is grateful for a Faculty of Biological Sciences PhD studentship funded by the University of Leeds. Juan O. Concha is grateful for a FAPESP Doctoral Scholarship (grant no.: 20/11900-6).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Alvim, Mr Jonas and Lima Silva Alvim, Mrs Fernanda
• Authors: Alvim, J. C., Bolt, R. M., An, J., Kamisugi, Y., Cuming, A., Silva-Alvim, F. A. L., Concha, J. O., daSilva, L. L. P., Hu, M., Hirsz, D., and Denecke, J.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in Nature Communications 14: 1612
• Publisher Policy: Reproduced under a Creative Commons License