USP4 inhibits SMAD4 monoubiquitination and promotes activin and BMP signaling
USP4 inhibits SMAD4 monoubiquitination and promotes activin and BMP signaling
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USP4 抑制 SMAD4 单泛素化并促进激活素和 BMP 信号转导
DOI：
10.15252/embj.201695372
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发表时间：
2017-06-01
期刊：
影响因子：
11.4
通讯作者：
ten Dijke, Peter
中科院分区：
文献类型：
--
作者：
Zhou, Fangfang;Xie, Feng;ten Dijke, Peter
SMAD 4是TGF-β家族细胞因子的常见细胞内效应子，但其活性动态调节的机制尚不清楚。我们证明，泛素特异性蛋白酶（USP）4强烈诱导激活素/BMP信号通过消除抑制性monoubiquitination从SMAD 4。这种修饰是由E3连接酶SMURF 2在配体诱导的调节性（R）-SMAD-SMAD 4复合物形成后募集至SMAD 4而触发的。尽管负调节因子c-SKI的相互作用抑制SMAD 4单泛素化，但配体刺激SMURF 2向c-SKI-SMAD 2复合物的募集并触发c-SKI泛素化和降解。因此，SMURF 2在TGF-b家族信号传导的终止和启动中起作用。在USP 4耗尽的小鼠胚胎干细胞（mESC）中单泛素化SMAD 4的增加降低了BMP和激活素诱导的胚胎干细胞命运的变化。在早期斑马鱼胚胎中，USP 4在激活素和BMP介导的形态发生事件中维持SMAD 4活性。此外，缺乏USP 4的斑马鱼表现出有缺陷的细胞迁移和较慢的协调细胞运动（称为外延），这两者都可以被SMAD 4拯救。因此，USP 4是SMAD 4活性的关键决定因素。
SMAD4 is a common intracellular effector for TGF-beta family cytokines, but the mechanism by which its activity is dynamically regulated is unclear. We demonstrated that ubiquitin-specific protease (USP) 4 strongly induces activin/BMP signaling by removing the inhibitory monoubiquitination from SMAD4. This modification was triggered by the recruitment of the E3 ligase, SMURF2, to SMAD4 following ligand-induced regulatory (R)-SMAD-SMAD4 complex formation. Whereas the interaction of the negative regulator c-SKI inhibits SMAD4 monoubiquitination, the ligand stimulates the recruitment of SMURF2 to the c-SKI-SMAD2 complex and triggers c-SKI ubiquitination and degradation. Thus, SMURF2 has a role in termination and initiation of TGF-b family signaling. An increase in monoubiquitinated SMAD4 in USP4-depleted mouse embryonic stem cells (mESCs) decreased both the BMP- and activin-induced changes in the embryonic stem cell fate. USP4 sustained SMAD4 activity during activin-and BMP-mediated morphogenic events in early zebrafish embryos. Moreover, zebrafish depleted of USP4 exhibited defective cell migration and slower coordinated cell movement known as epiboly, both of which could be rescued by SMAD4. Therefore, USP4 is a critical determinant of SMAD4 activity.