1. Cell Biology
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Ubiquitin-dependent folding of the Wnt signaling coreceptor LRP6

  1. Elsa Perrody
  2. Laurence Abrami
  3. Michal Feldman
  4. Beatrice Kunz
  5. Sylvie Urbé
  6. F Gisou van der Goot  Is a corresponding author
  1. Ecole Polytechnique Fédérale de Lausanne, Switzerland
  2. University of Liverpool, United Kingdom
Research Article
  • Cited 20
  • Views 1,648
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Cite this article as: eLife 2016;5:e19083 doi: 10.7554/eLife.19083

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

  1. Elsa Perrody

    Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  2. Laurence Abrami

    Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  3. Michal Feldman

    Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  4. Beatrice Kunz

    Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  5. Sylvie Urbé

    Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. 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.
    ORCID icon "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.

Reviewing Editor

  1. Matthew Freeman, University of Oxford, United Kingdom

Publication history

  1. Received: June 23, 2016
  2. Accepted: October 17, 2016
  3. Accepted Manuscript published: October 18, 2016 (version 1)
  4. Accepted Manuscript updated: October 20, 2016 (version 2)
  5. Version of Record published: November 9, 2016 (version 3)

Copyright

© 2016, Perrody et al.

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.

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