Audrey S. M. Chan, Thomas Clairfeuille, Euphemie Landao-Bassonga, Genevieve Kinna, Pei Ying Ng, Li Shen Loo, Tak Sum Cheng, Minghao Zheng, Wanjin Hong, Rohan D. Teasdale, Brett M. Collins, and Nathan J. Pavlos
The parathyroid hormone 1 receptor (PTHR) is central to the process of bone formation and remodelling. PTHR signaling requires receptor internalisation 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 mineralisation; contributing to profound skeletal deficits manifest in SNX27 knockout mice. Altogether, our data supports a critical role for SNX27-retromer mediated transport of PTHR in normal bone development.