The novel E3 ubiquitin ligase Tiul1 associates with TGIF to target Smad2 for degradation
The novel E3 ubiquitin ligase Tiul1 associates with TGIF to target Smad2 for degradation
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DOI：
10.1038/sj.emboj.7600398
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发表时间：
2004-09-29
期刊：
影响因子：
11.4
通讯作者：
Atfi, A
中科院分区：
文献类型：
--
作者：
Seo, SR;Lallemand, F;Atfi, A
泛素依赖的降解在转化生长因子-β信号的负调控中起着重要作用。在这里，我们确定了Tiul1(TGIF相互作用泛素连接酶1)，一个新的E3泛素连接酶，通过靶向激活的受体和Smad2的降解来抑制转化生长因子-β信号转导。Tiul1与Smad7结合，诱导激活的I型受体降解，而不影响Smad7的表达水平。当转化生长因子-β信号被激活时，Tiul1也可以与Smad2和核抑制因子TGIF相互作用。与Smad7一样，TGIF的稳态水平不受Tiul1的影响，但Tiul1与TGIF的相互作用允许这种泛素连接酶靶向Smad2进行降解。与此一致的是，过表达Tiul1抑制了转化生长因子-β诱导的生长停滞和转录反应。此外，siRNA沉默Tiul1或TGIF基因可抑制依赖于转化生长因子β的Smad2的降解，增强转化生长因子β介导的基因表达。这些结果揭示了TGIF作为泛素连接酶复合体的一个新的角色，该复合体介导了Smad2对转化生长因子-β信号的降解。
Ubiquitin-dependent degradation plays an important role in the negative regulation of TGF-beta signaling. Here, we identify Tiul1 ( for TGIF interacting ubiquitin ligase 1), a novel E3 ubiquitin ligase that inhibits TGF-beta signaling by targeting both the activated receptor and Smad2 for degradation. Tiul1 associates constitutively with Smad7 and induces degradation of the activated type I receptor without affecting the expression levels of Smad7. Tiul1 can also interact with Smad2 and the nuclear corepressor TGIF upon activation of TGF-beta signaling. Like Smad7, the steady-state levels of TGIF are not affected by Tiul1, but the interaction of Tiul1 with TGIF allows this ubiquitin ligase to target Smad2 for degradation. Consistent with this, overexpression of Tiul1 suppressed TGF-beta-induced growth arrest and transcriptional responses. In addition, silencing of Tiul1 or TGIF genes by siRNA resulted in suppression of the TGF-beta-dependent degradation of Smad2 and an enhancement of TGF-beta-mediated gene expression. These results reveal a new role for TGIF as a component of a ubiquitin ligase complex that mediates the degradation of Smad2 in response to TGF-beta signaling.