FAM/USP9x, a Deubiquitinating Enzyme Essential for TGFβ Signaling, Controls Smad4 Monoubiquitination
FAM/USP9x, a Deubiquitinating Enzyme Essential for TGFβ Signaling, Controls Smad4 Monoubiquitination
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DOI：
10.1016/j.cell.2008.10.051
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发表时间：
2009-01-09
期刊：
影响因子：
64.5
通讯作者：
Piccolo, Stefano
中科院分区：
文献类型：
--
作者：
Dupont, Sirio;Mamidi, Anant;Piccolo, Stefano
Smad复合体的组装对转化生长因子β信号转导至关重要，但对核Smad复合体失活或激活的机制知之甚少。通过siRNA筛选，我们鉴定了FAM(USP9X)，它是一种脱泛素酶，在TGFb和骨形态发生蛋白信号转导中起着必需的和进化上保守的成分。在体内，Smad4在赖氨酸519中是单价的，这种修饰通过阻止与磷酸化的Smad2的结合来抑制Smad4。FAM恢复了这一负面修改，重新启用了Smad4功能。FAM反对Ecotodermin/Tif1-Gamma(ECCO)的活性，这是一种核因子，我们现在明确了它的一个重要作用，即Smad4单核苷酸连接酶。我们的研究指出，Smad4单泛素化和去泛素化是细胞设置其转化生长因子β反应的一种方式：在几个模型系统中，FAM的丢失禁用了Smad4依赖的反应，而Ecto对FAM是上位的。这定义了一个调控Smads的泛素化步骤，该步骤与影响R-Smad磷酸化的步骤平行。
The assembly of the Smad complex is critical for TGF beta signaling, yet the mechanisms that inactivate or empower nuclear Smad complexes are less understood. By means of siRNA screen we identified FAM (USP9x), a deubiquitinase acting as essential and evolutionarily conserved component in TGFb and bone morphogenetic protein signaling. Smad4 is monoubiquitinated in lysine 519 in vivo, a modification that inhibits Smad4 by impeding association with phospho-Smad2. FAM reverts this negative modification, re-empowering Smad4 function. FAM opposes the activity of Ectodermin/Tif1 gamma (Ecto), a nuclear factor for which we now clarify a prominent role as Smad4 monoubiquitin ligase. Our study points to Smad4 monoubiquitination and deubiquitination as a way for cells to set their TGF beta responsiveness: loss of FAM disables Smad4-dependent responses in several model systems, with Ecto being epistatic to FAM. This defines a regulative ubiquitination step controlling Smads that is parallel to those impinging on R-Smad phosphorylation.