title: Control of the dynamics and homeostasis of the Drosophila Hedgehog receptor Patched by two C2-WW-HECT-E3 Ubiquitin ligases.
abstract: The conserved Hedgehog (HH) signals control animal development, adult stem cell maintenance and oncogenesis. In Drosophila, the HH co-receptor Patched (PTC) controls both HH gradient formation and signalling. PTC is post-translationally downregulated by HH, which promotes its endocytosis and destabilization, but the mechanisms of PTC trafficking and its importance in the control of PTC remain to be understood. PTC interacts with E3 Ubiquitin (UB)-ligases of the C2-WW-HECT family; two of them-SMURF and NEDD4-are known to regulate its levels. We demonstrate that mutation of the PTC PY motif, which mediates binding of C2-WW-HECT family members, inhibits its internalization but not its autonomous and non-autonomous signalling activities. In addition, we show that the two related UB-C2-WW-HECT ligases NEDD4 and SU(DX) regulate PTC trafficking and finely tune its accumulation through partially redundant but distinct functions. While both NEDD4 and SU(DX) promote PTC endocytosis, only SU(DX) is able to induce its lysosomal targeting and degradation. In conclusion, PTC trafficking and homeostasis are tightly regulated by a family of UB-ligases.
authors.affiliation: Institut Jacques Monod, CNRS, UMR 7592, University Paris Diderot, Sorbonne Paris Cité, Paris 75205, France.
authors.forename: Amira
authors.initials: A
authors.lastname: Brigui
authors.affiliation: Institut Jacques Monod, CNRS, UMR 7592, University Paris Diderot, Sorbonne Paris Cité, Paris 75205, France.
authors.forename: Line
authors.initials: L
authors.lastname: Hofmann
authors.affiliation: Institut Jacques Monod, CNRS, UMR 7592, University Paris Diderot, Sorbonne Paris Cité, Paris 75205, France.
authors.forename: Camilla
authors.initials: C
authors.lastname: Argüelles
authors.affiliation: Institut Jacques Monod, CNRS, UMR 7592, University Paris Diderot, Sorbonne Paris Cité, Paris 75205, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Sanial
authors.affiliation: Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Holmgren
authors.affiliation: Institut Jacques Monod, CNRS, UMR 7592, University Paris Diderot, Sorbonne Paris Cité, Paris 75205, France anne.plessis@ijm.fr.
authors.forename: Anne
authors.initials: A
authors.lastname: Plessis
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D006706:Homeostasis; D000075702:Nedd4 Ubiquitin Protein Ligases; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000502:physiology; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D002352:Carrier Proteins; D029721:Drosophila Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D011956:Receptors, Cell Surface; C070844:ptc protein, Drosophila; D000075702:Nedd4 Ubiquitin Protein Ligases; C000605755:Nedd4 protein, Drosophila; C492378:Smurf protein, Drosophila; C119838:Su(dx) protein, Drosophila; D044767:Ubiquitin-Protein Ligases
keywords: C2-WW-HECT Ubiquitin ligase; Drosophila; Hedgehog; Patched; intracellular protein trafficking; signal transduction