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

Jonas C. Alvim, Robert M. Bolt, Jing An, Yasuko Kamisugi, Andrew Cuming, Fernanda A. L. Silva-Alvim, Juan O. Concha, Luis L. P. daSilva, Meiyi Hu, Dominique Hirsz and Jurgen Denecke ()
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Jonas C. Alvim: University of Leeds
Robert M. Bolt: University of Leeds
Jing An: University of Leeds
Yasuko Kamisugi: University of Leeds
Andrew Cuming: University of Leeds
Fernanda A. L. Silva-Alvim: University of Leeds
Juan O. Concha: University of São Paulo, Ribeirão Preto
Luis L. P. daSilva: University of São Paulo, Ribeirão Preto
Meiyi Hu: University of Leeds
Dominique Hirsz: University of Leeds
Jurgen Denecke: University of Leeds

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37056-0

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