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VCP/p97 increases BMP signaling by accelerating ubiquitin ligase Smurf1 degradation
Author(s) -
Li Haiwen,
Cui Yu,
Wei Jun,
Liu Chao,
Chen Yuhan,
Cui Chun-Ping,
Li Lei,
Zhang Xueli,
Zhang Lingqiang
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201801173r
Subject(s) - ubiquitin ligase , ubiquitin , degradation (telecommunications) , microbiology and biotechnology , chemistry , cancer research , biochemistry , biology , computer science , gene , telecommunications
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 Smurfl and deliver the ubiquitinated Smurfl for degradation. Depletion of either p97 or NPL4 resulted in the elevation of Smurfl protein level and decreased BMP signaling accordingly. Mechanically, a typical proline, glutamic acid, serine, and threonine motif specifically existing in Smurfl 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 Smurfl degradation, thus increasing BMP signaling activity. Our findings first establish a link between p97 and Smurfl, providing an in‐depth understanding of how Smurfl 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. FASEB J. 33, 2928–2943 (2019). www.fasebj.org