SCFFBXL15 regulates BMP signalling by directing the degradation of HECT-type ubiquitin ligase Smurf1
SCFFBXL15 regulates BMP signalling by directing the degradation of HECT-type ubiquitin ligase Smurf1
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SCFFBXL15 通过指导 HECT 型泛素连接酶 Smurf1 的降解来调节 BMP 信号传导
DOI：
10.1038/emboj.2011.155
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发表时间：
2011-07-06
期刊：
影响因子：
11.4
通讯作者：
Zhang, Lingqiang
中科院分区：
文献类型：
--
作者：
Cui, Yu;He, Shan;Zhang, Lingqiang
Smad泛素化调节因子1（Smurf 1）是E6 AP C-末端（HECT）型E3泛素连接酶的同源物，在胚胎发育和骨重建中的骨形态发生蛋白（BMP）信号通路的调节中起关键作用。Smurf 1的稳定性和活性是如何受到负调控的，目前还不清楚。在这里，我们报告说，F-box和LRR结构域的蛋白15（FBXL 15），FBXL家族的F-box蛋白，形成一个Skp 1-Cullin 1-F-box蛋白-Roc 1（SCF）（FBXL 15）泛素连接酶复合物和目标Smurf 1的泛素化和蛋白酶体降解。FBXL 15通过其富含亮氨酸的重复结构域，特异性识别Smurf 1 HECT结构域的N叶内的大亚结构域，并促进Smurf 1在WW-HECT连接子区域内K355和K357上的泛素化。以这种方式，FBXL 15在哺乳动物细胞中正向调节BMP信号传导。通过特异性反义morpholinos敲低斑马鱼胚胎中fbxl 15的表达导致胚胎背侧化phenocoping BMP缺陷突变体。将FBXL 15 siRNA注射到大鼠骨组织中导致骨量的显著损失和骨矿物质密度的降低。总的来说，我们的研究结果表明，Smurf 1的稳定性受到SCFFBXL 15介导的泛素化的抑制，FBXL 15是胚胎发育和成人骨形成过程中BMP信号传导的关键调节因子。The EMBO Journal（2011）30，2675-2689. doi：10.1038/emboj.2011.155;在线发布2011年5月13日
Smad ubiquitination regulatory factor 1 (Smurf1), an homologous to E6AP C-terminus (HECT)-type E3 ubiquitin ligase, performs a crucial role in the regulation of the bone morphogenetic protein (BMP) signalling pathway in both embryonic development and bone remodelling. How the stability and activity of Smurf1 are negatively regulated remains largely unclear. Here, we report that F-box and LRR domain-containing protein 15 (FBXL15), an F-box protein of the FBXL family, forms an Skp1-Cullin1-F-box protein-Roc1 (SCF)(FBXL15) ubiquitin ligase complex and targets Smurf1 for ubiquitination and proteasomal degradation. FBXL15, through its leucine-rich repeat domain, specifically recognizes the large subdomain within the N-lobe of the Smurf1 HECT domain and promotes the ubiquitination of Smurf1 on K355 and K357 within the WW-HECT linker region. In this way, FBXL15 positively regulates BMP signalling in mammalian cells. Knockdown of fbxl15 expression in zebrafish embryos by specific antisense morpholinos causes embryonic dorsalization phenocoping BMP-deficient mutants. Injection of FBXL15 siRNAs into rat bone tissues leads to a significant loss of bone mass and decrease in bone mineral density. Collectively, our results demonstrate that Smurf1 stability is suppressed by SCFFBXL15 -mediated ubiquitination and that FBXL15 is a key regulator of BMP signalling during embryonic development and adult bone formation. The EMBO Journal (2011) 30, 2675-2689. doi:10.1038/emboj.2011.155; Published online 13 May 2011