Abstract
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.
Original language | English |
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Pages (from-to) | 4211-4221 |
Number of pages | 11 |
Journal | Oncotarget |
Volume | 5 |
Issue number | 12 |
DOIs | |
Publication status | Published - 2014 |
Externally published | Yes |
Keywords
- CYLD
- Degradation
- Phosphorylation
- Tumor suppressor
- Ubiquitination
- β-TRCP
ASJC Scopus subject areas
- Oncology