Retromer in Osteoblasts Interacts With Protein Phosphatase 1 Regulator Subunit 14C, Terminates Parathyroid Hormone's Signaling, and Promotes Its Catabolic Response.
Retromer in Osteoblasts Interacts With Protein Phosphatase 1 Regulator Subunit 14C, Terminates Parathyroid Hormone's Signaling, and Promotes Its Catabolic Response.
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DOI：
10.1016/j.ebiom.2016.05.028
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发表时间：
2016-07
期刊：
影响因子：
11.1
通讯作者：
Xiong WC
中科院分区：
文献类型：
--
作者：
Xiong L;Xia WF;Tang FL;Pan JX;Mei L;Xiong WC
甲状旁腺激素 (PTH) 在骨重塑中发挥着关键但独特的作用，包括骨形成（合成代谢反应）和骨吸收（分解代谢反应）。尽管其信号传导和功能已被广泛研究，但人们才刚刚开始了解 PTH 激活常见受体（PTH 1 型受体 (PTH1R)）如何诱导不同的功能，以及 PTH1R 信号传导如何终止。在这里，我们提供了液泡蛋白分选 35 (VPS35)（逆转录酶的主要成分）在调节 PTH1R 运输、关闭 PTH 信号传导和促进其分解代谢功能方面的证据。 VPS35 在成骨细胞 (OB) 谱系细胞中表达。 OB 中的 VPS35 缺陷会损害 PTH(1–34) 促进的 PTH1R 易位至跨高尔基体网络，增强 PTH(1–34) 驱动的信号传导，并降低培养物和小鼠中 PTH(1–34) 的分解代谢反应。进一步的机械研究表明，VPS35 不仅与 PTH1R 相互作用，还与蛋白磷酸酶 1 调节亚基 14C (PPP1R14C)（PP1 磷酸酶的抑制亚基）相互作用。 PPP1R14C 还与 PTH1R 相互作用，这对于 VPS35 缺陷的 OB 谱系细胞中内体 PTH1R 信号传导的增加和 PTH(1–34) 分解代谢反应的减少是必需的。综上所述，这些结果表明 VPS35 可能通过与 PTH1R 和 PPP1R14C 的相互作用来解除 PTH1R 信号传导的调节。该事件对于 PTH(1-34) 信号动力学的控制至关重要，这可能是 PTH 诱导的分解代谢反应和适当的骨重塑的基础。 VPS35 终止 PTH(1-34) 诱导的细胞表面和内体信号传导 成骨细胞 VPS35 促进 PTH(1-34) 驱动的分解代谢反应 VPS35 与 PPP1R14C 相互作用 PPP1R14C 还与 PTH1R 相互作用并促进 PTH(1-34) 诱导的内体信号传导 PPP1R14C 对于增加内体 PTH1R 信号传导和减少VPS35 缺陷的 OB 谱系细胞中 PTH(1-34) 的分解代谢反应
Parathyroid hormone (PTH) plays critical, but distinct, roles in bone remodeling, including bone formation (anabolic response) and resorption (catabolic response). Although its signaling and function have been extensively investigated, it just began to be understood how distinct functions are induced by PTH activating a common receptor, the PTH type 1 receptor (PTH1R), and how PTH1R signaling is terminated. Here, we provide evidence for vacuolar protein sorting 35 (VPS35), a major component of retromer, in regulating PTH1R trafficking, turning off PTH signaling, and promoting its catabolic function. VPS35 is expressed in osteoblast (OB)-lineage cells. VPS35-deficiency in OBs impaired PTH(1–34)-promoted PTH1R translocation to the trans-Golgi network, enhanced PTH(1–34)-driven signaling, and reduced PTH(1–34)'s catabolic response in culture and in mice. Further mechanical studies revealed that VPS35 interacts with not only PTH1R, but also protein phosphatase 1 regulatory subunit 14C (PPP1R14C), an inhibitory subunit of PP1 phosphatase. PPP1R14C also interacts with PTH1R, which is necessary for the increased endosomal PTH1R signaling and decreased PTH(1–34)'s catabolic response in VPS35-deficient OB-lineage cells. Taken together, these results suggest that VPS35 deregulates PTH1R-signaling likely by its interaction with PTH1R and PPP1R14C. This event is critical for the control of PTH(1–34)-signaling dynamics, which may underlie PTH-induced catabolic response and adequate bone remodeling. VPS35 terminates PTH(1-34)-induced cell surface and endosomal signalings Osteoblastic VPS35 promotes PTH(1-34)-driven catabolic response VPS35 interacts with PPP1R14C PPP1R14C also interacts with PTH1R and promotes PTH(1-34)-induced endosomal signaling PPP1R14C is necessary for the increased endosomal PTH1R signaling and decreased PTH(1-34)’s catabolic response in VPS35-deficient OB-lineage cells