Ubiquitin-dependent folding of the Wnt signaling coreceptor LRP6

Abstract
Article and author information
Metrics

Abstract

Many membrane proteins fold inefficiently and require the help of enzymes and chaperones. Here we reveal a novel folding assistance system that operates on membrane proteins from the cytosolic side of the endoplasmic reticulum (ER). We show that folding of the Wnt signaling coreceptor LRP6 is promoted by ubiquitination of a specific lysine, retaining it in the ER while avoiding degradation. Subsequent ER exit requires removal of ubiquitin from this lysine by the deubiquitinating enzyme USP19. This ubiquitination-deubiquitination is conceptually reminiscent of the glucosylation-deglucosylation occurring in the ER lumen during the calnexin/calreticulin folding cycle. To avoid infinite futile cycles, folded LRP6 molecules undergo palmitoylation and ER export, while unsuccessfully folded proteins are, with time, polyubiquitinated on other lysines and targeted to degradation. This ubiquitin-dependent folding system also controls the proteostasis of other membrane proteins as CFTR and anthrax toxin receptor 2, two poor folders involved in severe human diseases.

Article and author information

Author details

Elsa Perrody

Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Competing interests
The authors declare that no competing interests exist.
Laurence Abrami

Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Competing interests
The authors declare that no competing interests exist.
Michal Feldman

Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Competing interests
The authors declare that no competing interests exist.
Beatrice Kunz

Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Competing interests
The authors declare that no competing interests exist.
Sylvie Urbé

Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom

Competing interests
The authors declare that no competing interests exist.
F Gisou van der Goot

Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

For correspondence
gisou.vandergoot@epfl.ch

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8522-274X

Funding

European Research Council (340260 PalmERa)

Laurence Abrami

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (van der Goot)

Gisou van der Goot

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.