SCFβ-TRCP regulates osteoclastogenesis via promoting CYLD ubiquitination.
SCFβ-TRCP regulates osteoclastogenesis via promoting CYLD ubiquitination.
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DOI：
10.18632/oncotarget.1971
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发表时间：
2014-06-30
期刊：
影响因子：
--
通讯作者：
Wei W
中科院分区：
文献类型：
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作者：
Wu X;Fukushima H;North BJ;Nagaoka Y;Nagashima K;Deng F;Okabe K;Inuzuka H;Wei W
CyLD主要通过拮抗κ受体相关因子(TRAF)介导的破骨细胞前体细胞中K63连接的泛素化，对NF-TRAF B信号通路和破骨细胞分化具有负性调节作用。细胞色素B激酶(IκB Kinase，IKK)控制着细胞色素D酶的活性，但控制细胞色素D蛋白稳定性的分子机制(S)在很大程度上仍不清楚。在这里，我们报道了干细胞因子β-TrCP调节CyLD的泛素化和降解，这一过程依赖于IKK先前在Ser432/Ser436处对CyLD的磷酸化。此外，缺失β-TrCP可诱导破骨细胞前体细胞内CyLD积聚和TRAF6去泛素化，从而抑制RANKL诱导的破骨细胞分化。因此，这些数据表明IKK/β-TrCP/CyLD信号通路是破骨细胞发生的重要调节因子。
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.