title: Sorting nexin 27 couples PTHR trafficking to retromer for signal regulation in osteoblasts during bone growth.
abstract: The parathyroid hormone 1 receptor (PTHR) is central to the process of bone formation and remodeling. PTHR signaling requires receptor internalization into endosomes, which is then terminated by recycling or degradation. Here we show that sorting nexin 27 (SNX27) functions as an adaptor that couples PTHR to the retromer trafficking complex. SNX27 binds directly to the C-terminal PDZ-binding motif of PTHR, wiring it to retromer for endosomal sorting. The structure of SNX27 bound to the PTHR motif reveals a high-affinity interface involving conserved electrostatic interactions. Mechanistically, depletion of SNX27 or retromer augments intracellular PTHR signaling in endosomes. Osteoblasts genetically lacking SNX27 show similar disruptions in PTHR signaling and greatly reduced capacity for bone mineralization, contributing to profound skeletal deficits in SNX27-knockout mice. Taken together, our data support a critical role for SNX27-retromer mediated transport of PTHR in normal bone development.
authors.affiliation: Cellular Orthopaedic Laboratory, School of Surgery, University of Western Australia, Nedlands 6009, Australia.
authors.forename: Audrey S M
authors.initials: AS
authors.lastname: Chan
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, St. Lucia 4072, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Clairfeuille
authors.affiliation: Cellular Orthopaedic Laboratory, School of Surgery, University of Western Australia, Nedlands 6009, Australia.
authors.forename: Euphemie
authors.initials: E
authors.lastname: Landao-Bassonga
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, St. Lucia 4072, Australia.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Kinna
authors.affiliation: Cellular Orthopaedic Laboratory, School of Surgery, University of Western Australia, Nedlands 6009, Australia.
authors.forename: Pei Ying
authors.initials: PY
authors.lastname: Ng
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR, Singapore 138673.
authors.forename: Li Shen
authors.initials: LS
authors.lastname: Loo
authors.affiliation: Cellular Orthopaedic Laboratory, School of Surgery, University of Western Australia, Nedlands 6009, Australia.
authors.forename: Tak Sum
authors.initials: TS
authors.lastname: Cheng
authors.affiliation: Cellular Orthopaedic Laboratory, School of Surgery, University of Western Australia, Nedlands 6009, Australia.
authors.forename: Minghao
authors.initials: M
authors.lastname: Zheng
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR, Singapore 138673.
authors.forename: Wanjin
authors.initials: W
authors.lastname: Hong
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, St. Lucia 4072, Australia.
authors.forename: Rohan D
authors.initials: RD
authors.lastname: Teasdale
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, St. Lucia 4072, Australia nathan.pavlos@uwa.edu.au b.collins@imb.uq.edu.au.
authors.forename: Brett M
authors.initials: BM
authors.lastname: Collins
authors.affiliation: Cellular Orthopaedic Laboratory, School of Surgery, University of Western Australia, Nedlands 6009, Australia nathan.pavlos@uwa.edu.au b.collins@imb.uq.edu.au.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Pavlos
mesh_terms: D000818:Animals; D001846:Bone Development / Q000235:genetics / Q000502:physiology*; D016723:Bone Remodeling / Q000502:physiology; D002113:Calcification, Physiologic / Q000235:genetics / Q000502:physiology; D011992:Endosomes / Q000378:metabolism; D057809:HEK293 Cells / Q000378:metabolism; D006801:Humans; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D054731:PDZ Domains; D010281:Parathyroid Hormone / Q000494:pharmacology; D021381:Protein Transport; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058305:Sorting Nexins / Q000235:genetics / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D010281:Parathyroid Hormone; D044168:Receptor, Parathyroid Hormone, Type 1; C500393:Snx27 protein, mouse; D058305:Sorting Nexins