Sorting nexin 27 couples PTHR trafficking to retromer for signal regulation in osteoblasts during bone growth.
Sorting nexin 27 couples PTHR trafficking to retromer for signal regulation in osteoblasts during bone growth.
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DOI：
10.1091/mbc.e15-12-0851
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发表时间：
2016-04-15
影响因子：
3.3
通讯作者：
Pavlos NJ
中科院分区：
文献类型：
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作者：
Chan AS;Clairfeuille T;Landao-Bassonga E;Kinna G;Ng PY;Loo LS;Cheng TS;Zheng M;Hong W;Teasdale RD;Collins BM;Pavlos NJ
内吞蛋白SNX27的功能是将甲状旁腺激素受体(PTHR)连接到逆转录转运复合体。SNX27基因缺失会导致PTHR信号过度活跃，导致生后骨生长过程中成骨细胞成骨减少。因此，SNX27是一种新的PTHR信号调制器。甲状旁腺激素1受体(PTHR)是骨形成和改建过程的中心。PTHR信号需要受体内化到内吞体内，然后通过循环或降解终止。在这里，我们证明了分类连接蛋白27(SNX27)作为一个接头将PTHR偶联到逆转录转运复合体。SNX27直接与PTHR的C-末端PDZ结合基序结合，将其连接到逆转录聚体进行内体分选。SNX27与PTHR基序结合的结构显示了一个包含保守的静电相互作用的高亲和力界面。从机制上讲，SNX27的缺失或逆转录增加了内体中的细胞内PTHR信号。SNX27基因缺失的成骨细胞表现出类似的PTHR信号中断，并极大地降低了骨矿化能力，导致SNX27基因敲除小鼠严重的骨骼缺陷。综上所述，我们的数据支持SNX27-逆转聚体介导的PTHR在正常骨发育中的关键作用。
The endocytic protein SNX27 functions to link the parathyroid hormone receptor (PTHR) to the retromer trafficking complex. Loss of SNX27 in mice leads to overactive PTHR signaling and reduced osteoblastic bone formation during postnatal bone growth. Thus SNX27 is a new modulator of PTHR signaling. 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.