title: Ubiquitin-dependent folding of the Wnt signaling coreceptor LRP6.
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.
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Elsa
authors.initials: E
authors.lastname: Perrody
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Laurence
authors.initials: L
authors.lastname: Abrami
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Michal
authors.initials: M
authors.lastname: Feldman
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Kunz
authors.affiliation: Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Urbé
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: F Gisou
authors.identifier: 0000-0002-8522-274X
authors.initials: FG
authors.lastname: van der Goot
mesh_terms: D002460:Cell Line; D010450:Endopeptidases / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000737:chemistry* / Q000378:metabolism*; D017510:Protein Folding; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D025801:Ubiquitin; D010450:Endopeptidases; C559917:USP19 protein, human
keywords: ERAD; cell biology; endoplasmic; folding; human; transmembrane; ubiquitin