Sorting nexin 27 couples PTHR trafficking to retromer for signal regulation in osteoblasts during bone growth

Audrey Chan, T. Clairfeuille, Euphemie Landao-Bassonga, G. Kinna, Pei Ying Ng, L.S. Loo, Tak Sum Cheng, Minghao Zheng, W. Hong, R.D. Teasdale, B.M. Collins, Nathan Pavlos

    Research output: Contribution to journalArticle

    23 Citations (Scopus)

    Abstract

    © 2016 Billmann, Horn, et al. 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.
    Original languageEnglish
    Pages (from-to)1367-1382
    Number of pages16
    JournalMolecular Biology of the Cell
    Volume27
    Issue number8
    DOIs
    Publication statusPublished - 15 Apr 2016

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