VCP/p97 increases BMP signaling by accelerating ubiquitin ligase Smurf1 degradation
VCP/p97 increases BMP signaling by accelerating ubiquitin ligase Smurf1 degradation
复制标题
VCP/p97 通过加速泛素连接酶 Smurf1 降解来增强 BMP 信号传导
DOI：
10.1096/fj.201801173r
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发表时间：
2019-02-01
期刊：
影响因子：
4.8
通讯作者：
Zhang, Lingqiang
中科院分区：
文献类型：
--
作者：
Li, Haiwen;Cui, Yu;Zhang, Lingqiang
骨形态发生蛋白（BMP）-Smad信号通路通过调节成骨细胞活性在控制骨稳态中发挥着至关重要的作用。众所周知，泛素连接酶 Smad 泛素化调节因子 (Smurf)1 是 BMP 信号传导的主要负调节因子，但其稳定性和活性如何调节仍知之甚少。我们的研究表明，含有 valosin 的蛋白/p97（其突变导致罕见形式的佩吉特骨病 (PDB) 样综合征，例如与佩吉特骨病和额颞叶痴呆 (IBM-PFD) 相关的包涵体肌病 (IBM-PFD)）及其适配器核蛋白定位 (NPL)4，与 Smurf1 特异性相互作用并传递 泛素化 Smurf1 进行降解。 p97 或 NPL4 的缺失会导致 Smurf1 蛋白水平升高并相应降低 BMP 信号传导。从机械角度来说，Smurf1 中特有的典型脯氨酸、谷氨酸、丝氨酸和苏氨酸基序是 p97 识别和降解所必需的，并且该过程依赖于 p97 ATP 酶活性。更重要的是，与p97 WT相比，p97的PDB相关突变（主要是A232E）具有p97更高的ATP酶活性，进一步促进了Smurf1降解，从而增加了BMP信号活性。我们的研究结果首先建立了p97和Smurf1之间的联系，为Smurf1的调控方式以及p97相关骨病的机制提供了深入的了解。Li, H., Cui, Y., Wei, J., Liu, C., Chen, Y., Cui, C.-P., Li, L., Zhuang, X., Zhuang, L. VCP/p97增加 BMP 信号通过加速泛素连接酶 Smurf1 降解。
The bone morphogenetic protein (BMP)-Smad signaling pathway plays a crucial role in the control of bone homeostasis by regulating osteoblast activity. It is known that the ubiquitin ligase Smad ubiquitination regulatory factor (Smurf)1 is a master negative regulator of BMP signaling, but how its stability and activity are regulated remains poorly understood. Our study showed that valosin-containing protein/p97, the mutations of which lead to rare forms of Paget's disease of bone (PDB)-like syndromesuch as inclusion body myopathy (IBM) associated with Paget's disease of bone and frontotemporal dementia (IBM-PFD)together with its adaptor nuclear protein localization (NPL)4, specifically interact with Smurf1 and deliver the ubiquitinated Smurf1 for degradation. Depletion of either p97 or NPL4 resulted in the elevation of Smurf1 protein level and decreased BMP signaling accordingly. Mechanically, a typical proline, glutamic acid, serine, and threonine motif specifically existing in Smurf1 is necessary for its recognition and degradation by p97, and this process is dependent on p97 ATPase activity. More importantly, compared with p97 WT, PDB-associated mutation of p97 (mainly A232E) harboring the higher ATPase activity of p97 further promoted Smurf1 degradation, thus increasing BMP signaling activity. Our findings first establish a link between p97 and Smurf1, providing an in-depth understanding of how Smurf1 is regulated, as well as the mechanism of p97-related bone diseases.Li, H., Cui, Y., Wei, J., Liu, C., Chen, Y., Cui, C.-P., Li, L., Zhang, X., Zhang, L. VCP/p97 increases BMP signaling by accelerating ubiquitin ligase Smurf1 degradation.