title: The conserved transmembrane RING finger protein PLR-1 downregulates Wnt signaling by reducing Frizzled, Ror and Ryk cell-surface levels in C. elegans.
abstract: Wnts control a wide range of essential developmental processes, including cell fate specification, axon guidance and anteroposterior neuronal polarization. We identified a conserved transmembrane RING finger protein, PLR-1, that governs the response to Wnts by lowering cell-surface levels of the Frizzled family of Wnt receptors in Caenorhabditis elegans. Loss of PLR-1 activity in the neuron AVG causes its anteroposterior polarity to be symmetric or reversed because signaling by the Wnts CWN-1 and CWN-2 are inappropriately activated, whereas ectopic PLR-1 expression blocks Wnt signaling and target gene expression. Frizzleds are enriched at the cell surface; however, when PLR-1 and Frizzled are co-expressed, Frizzled is not detected at the surface but instead is colocalized with PLR-1 in endosomes. The Frizzled cysteine-rich domain (CRD) and invariant second intracellular loop lysine are crucial for PLR-1 downregulation. The PLR-1 RING finger and protease-associated (PA) domain are essential for activity. In a Frizzled-dependent manner, PLR-1 reduces surface levels of the Wnt receptors CAM-1/Ror and LIN-18/Ryk. PLR-1 is a homolog of the mammalian transmembrane E3 ubiquitin ligases RNF43 and ZNRF3, which control Frizzled surface levels in an R-spondin-sensitive manner. We propose that PLR-1 downregulates Wnt receptor surface levels via lysine ubiquitylation of Frizzled to coordinate spatial and temporal responses to Wnts during neuronal development.
authors.affiliation: Molecular Neurobiology Program, Department of Pharmacology, Skirball Institute, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Moffat
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Robinson
authors.forename: Anastasia
authors.initials: A
authors.lastname: Bakoulis
authors.forename: Scott G
authors.initials: SG
authors.lastname: Clark
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D002465:Cell Movement; D016764:Cell Polarity; D017124:Conserved Sequence; D003600:Cytosol / Q000378:metabolism; D015536:Down-Regulation; D011992:Endosomes / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D017433:Protein Structure, Secondary; D054829:RING Finger Domains; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000378:metabolism; D013329:Structure-Activity Relationship; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: D029742:Caenorhabditis elegans Proteins; D008565:Membrane Proteins; C108315:Mom-5 protein, C elegans; D049452:Green Fluorescent Proteins; C000596117:PLR-1 protein, C elegans; D044767:Ubiquitin-Protein Ligases; C526267:CAM-1 protein, C elegans; C492691:LIN-18 protein, C elegans; D020794:Receptor Protein-Tyrosine Kinases; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D008239:Lysine
keywords: C. elegans; Membrane protein trafficking; Neuronal polarity; Wnt signaling