State Key Laboratory of Proteomics, National Center of Protein Sciences, Beijing Institute of Lifeomics, Beijing, China.
Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
FASEB J. 2019 Feb;33(2):2928-2943. doi: 10.1096/fj.201801173R. Epub 2018 Oct 18.
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 syndrome-such 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.
骨形态发生蛋白（BMP）-Smad 信号通路在调节成骨细胞活性以控制骨稳态中起着至关重要的作用。已知泛素连接酶 Smad 泛素化调节因子（Smurf）1 是 BMP 信号的主要负调控因子，但它的稳定性和活性如何调节仍知之甚少。我们的研究表明，含有缬氨酸的蛋白/p97（其突变导致罕见形式的 Pagets 骨病（PDB）样综合征，如伴有 Pagets 骨病和额颞叶痴呆的包涵体肌病（IBM-PFD））与它的衔接核蛋白定位（NPL）4 一起，特异性地与 Smurf1 相互作用，并将泛素化的 Smurf1 递送给降解。消耗 p97 或 NPL4 会导致 Smurf1 蛋白水平升高，相应地降低 BMP 信号。在机制上，Smurf1 中特有的一个脯氨酸、谷氨酸、丝氨酸和苏氨酸基序对于 p97 的识别和降解是必需的，这个过程依赖于 p97 ATP 酶活性。更重要的是，与 p97 WT 相比，具有更高 p97 ATP 酶活性的与 PDB 相关的 p97 突变（主要是 A232E）进一步促进了 Smurf1 的降解，从而增加了 BMP 信号活性。我们的发现首次在 p97 和 Smurf1 之间建立了联系，深入了解了 Smurf1 是如何被调节的，以及 p97 相关骨病的机制。-李，H.，崔，Y.，魏，J.，刘，C.，陈，Y.，崔，C.-P.，李，L.，张，X.，张，L. VCP/p97 通过加速泛素连接酶 Smurf1 降解来增加 BMP 信号。
