RANKL induces NFATc1 acetylation and stability via histone acetyltransferases during osteoclast differentiation
RANKL induces NFATc1 acetylation and stability via histone acetyltransferases during osteoclast differentiation
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DOI：
10.1042/bj20110062
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发表时间：
2011-06-01
影响因子：
4.1
通讯作者：
Kim, Nacksung
中科院分区：
文献类型：
--
作者：
Kim, Jung Ha;Kim, Kabsun;Kim, Nacksung
NFATc 1（nuclear factor of activated T-cells c1，活化T细胞核因子c1）是一种关键的转录因子，在调节破骨细胞特异性下游靶基因如TRAP（tartrate-resistant acid phosphatase，抗酒石酸酸性磷酸酶）和OSCAR（osteoclast-associated receptor，破骨细胞相关受体）的表达中起重要作用。研究表明，RANKL [NF-κ B（核因子κ B）配体的受体激活剂]在破骨细胞生成过程中在转录水平诱导NFATc 1表达。在本研究中，我们证明RANKL通过翻译后修饰增加NFATc 1蛋白水平。RANKL通过HAT（组蛋白乙酰转移酶），如p300和PCAF [p300/CREB（cAMP反应元件结合蛋白）结合蛋白相关因子]刺激NFATc 1乙酰化，从而稳定NFATc 1蛋白。PCAF与NFATc 1物理相互作用，直接诱导NFATc 1乙酰化和稳定性，随后增加NFATc 1的转录活性。此外，RANKL介导的NFATc 1乙酰化通过HDAC（组蛋白脱乙酰酶）抑制剂丁酸钠和scriptaid增加。HDAC 5的过表达降低了RANKL或PCAF介导的NFATc 1乙酰化、稳定性和反式激活活性，表明HAT和HDAC活性之间的平衡可能在NFATc 1水平的调节中发挥作用。此外，RANKL和p300诱导PCAF乙酰化和稳定性，从而增强NFATc 1的转录活性。通过siRNA（小干扰RNA）下调PCAF可降低NFATc 1乙酰化和稳定性，以及RANKL诱导的破骨细胞生成。综上所述，本研究的结果表明，RANKL诱导HAT介导的NFATc 1乙酰化和稳定性，随后在破骨细胞分化过程中增加NFATc 1的转录活性。
NFATc1 (nuclear factor of activated T-cells c1), a key transcription factor, plays a role in regulating expression of osteoclast-specific downstream target genes such as TRAP (tartrate-resistant acid phosphatase) and OSCAR (osteoclast-associated receptor). It has been shown that RANKL [receptor activator of NF-kappa B (nuclear factor kappa B) ligand] induces NFATc1 expression during osteoclastogenesis at a transcriptional level. In the present study, we demonstrate that RANKL increases NFATc1 protein levels by post-translational modification. RANKL stimulates NFATc1 acetylation via HATs (histone acetyltransferases), such as p300 and PCAF [p300/CREB (cAMP-response-element-binding protein)-binding protein-associated factor], thereby stabilizing NFATc1 proteins. PCAF physically interacts with NFATc1 and directly induces NFATc1 acetylation and stability, subsequently increasing the transcriptional activity of NFATc1. In addition, RANKL-mediated NFATc1 acetylation is increased by the HDAC (histone deacetylase) inhibitors sodium butyrate and scriptaid. Overexpression of HDAC5 reduces RANKL- or PCAF-mediated NFATc1 acetylation, stability and transactivation activity, suggesting that the balance between HAT and HDAC activities might play a role in the regulation of NFATc1 levels. Furthermore, RANKL and p300 induce PCAF acetylation and stability, thereby enhancing the transcriptional activity of NFATc1. Down-regulation of PCAF by siRNA (small interfering RNA) decreases NFATc1 acetylation and stability, as well as RANKL-induced osteoclastogenesis. Taken together, the results of the present study demonstrate that RANKL induces HAT-mediated NFATc1 acetylation and stability, and subsequently increases the transcriptional activity of NFATc1 during osteoclast differentiation.