Ubiquitin-dependent folding of the Wnt signaling coreceptor LRP6.

Elsa Perrody,F Gisou Van Der Goot,Michal Feldman,Sylvie Urbé,Beatrice Kunz,Laurence Abrami

doi:10.7554/elife.19083

Elsa Perrody, F Gisou Van Der Goot + Show 4 more

Open Access

https://doi.org/10.7554/elife.19083

Copy DOI

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.

Highlights

While protein folding may be extremely efficient, the presence of multiple domains, in soluble or membrane proteins, greatly reduces the efficacy of the overall process
We show that following synthesis, lipoprotein Receptor-related Protein 6 (LRP6) undergoes ubiquitination on Lys-1403, most likely of a specific form
Upon release from this putative ubiquitin-binding chaperone, LRP6 is deubiquitinated by USP19

Summary

Introduction

While protein folding may be extremely efficient, the presence of multiple domains, in soluble or membrane proteins, greatly reduces the efficacy of the overall process. An illustrative example of folding inefficiency, and the consequences thereof, is the Cystic Fibrosis Transmembrane Regulator (CFTR), a chloride channel expressed at the surface of lung epithelial cells (Riordan, 2008). When the number of functional CFTR channels is further reduced, patients suffer from Cystic Fibrosis (Riordan, 2008). This is the case for mutations that affect the kinetics or thermodynamics of CFTR folding in the ER, such as the most frequent CF mutation DF508, and which are recognized by ER quality control systems and targeted for degradation (Riordan, 2008)

Methods

Results

Conclusion