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.
CITATION STYLE
Wu, X., Fukushima, H., North, B. J., Nagaoka, Y., Nagashima, K., Deng, F., … Wei, W. (2014). SCFβ-TRCP regulates osteoclastogenesis via promoting CYLD ubiquitination. Oncotarget, 5(12), 4211–4221. https://doi.org/10.18632/oncotarget.1971
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