SCFβ-TRCP regulates osteoclastogenesis via promoting CYLD ubiquitination
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Xiaomian Wu1,2,*, Hidefumi Fukushima2,3,*, Brian J. North2, Yoshiyuki Nagaoka3, Katsuyuki Nagashima3, Feng Deng1, Koji Okabe3, Hiroyuki Inuzuka2 and Wenyi Wei2
1 Chongqing key Laboratory for Oral Diseases and Biomedical Sciences, The Affiliated Hospital of Stomatology, Chongqing Medical University, Chongqing, P.R. China
2 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
3 Department of Physiological Sciences and Molecular Biology, Fukuoka Dental College, Fukuoka, Japan
* These authors contributed equally to this work
Hiroyuki Inuzuka, email:
Wenyi Wei, email:
Keywords: β-TRCP, CYLD, tumor suppressor, degradation, phosphorylation, ubiquitination
Received: April 1, 2014 Accepted: May 12, 2014 Published: May 14, 2014
CYLD negatively regulates the NF-κB signaling pathway and osteoclast differentiation largely through antagonizing TNF receptor-associated factor (TRAF)-mediated K63-linkage polyubiquitination in osteoclast precursor cells. CYLD activity is controlled by IκB kinase (IKK), but the molecular mechanism(s) governing CYLD protein stability remains largely undefined. Here, we report that SCFβ-TRCP regulates the ubiquitination and degradation of CYLD, a process dependent on prior phosphorylation of CYLD at Ser432/Ser436 by IKK. Furthermore, depletion of β-TRCP induced CYLD accumulation and TRAF6 deubiquitination in osteoclast precursor cells, leading to suppression of RANKL-induced osteoclast differentiation. Therefore, these data pinpoint the IKK/β-TRCP/CYLD signaling pathway as an important modulator of osteoclastogenesis.
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