title: Palmitoylation and ubiquitination regulate exit of the Wnt signaling protein LRP6 from the endoplasmic reticulum.
abstract: Canonical Wnt signaling is initiated by binding of Wnt proteins to members of the Frizzled family and subsequent complex formation with lipoprotein receptor-related proteins 5/6 (LRP5/6). Here, we show that LRP6 is palmitoylated on a juxtamembranous cysteine and that palmitoylation is required for exit from the endoplasmic reticulum (ER). We propose that palmitoylation serves to tilt the long, 23-residue transmembrane domain of LRP6 with respect to the plane of membrane to prevent a hydrophobic mismatch and subsequent recognition by the ER quality control. In support of this model, a palmitoylation-deficient LRP6 mutant could be rescued from ER retention by deletion of two to four residues in the transmembrane domain. Importantly, we found that palmitoylation-deficient LRP6 was retained in the ER by a completely novel monoubiquitination-dependent ER retention mechanism. Mutation of a specific lysine indeed abolished ubiquitination of palmitoylation-deficient LRP6 and led to a rescue from ER retention. Finally, at the cell surface, we found that interplay between palmitoylation and ubiquitination was necessary for efficient Wnt signaling.
authors: Global Health Institute, Faculty of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Station 15, CH-1015 Lausanne, Switzerland.
authors: Laurence
authors: L
authors: Abrami
authors: Béatrice
authors: B
authors: Kunz
authors: Ioan
authors: I
authors: Iacovache
authors: F Gisou
authors: FG
authors: van der Goot
mesh_terms: D000595:Amino Acid Sequence; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000378:metabolism*; D054878:Lipoylation / Q000502:physiology*; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D015398:Signal Transduction; D014162:Transfection; D054875:Ubiquitination / Q000502:physiology*; D051153:Wnt Proteins
chemical_list: D026502:LDL-Receptor Related Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051153:Wnt Proteins