OTUB1 enhances TGFβ signalling by inhibiting the ubiquitylation and degradation of active SMAD2/3.
OTUB1 enhances TGFβ signalling by inhibiting the ubiquitylation and degradation of active SMAD2/3.
复制标题
DOI：
10.1038/ncomms3519
复制
发表时间：
2013
影响因子：
16.6
通讯作者：
Sapkota, Gopal P.
中科院分区：
文献类型：
--
作者：
Herhaus, Lina;Al-Salihi, Mazin;Macartney, Thomas;Weidlich, Simone;Sapkota, Gopal P.
SMAD转录因子是TGFβ细胞因子的关键细胞内转导因子。SMAD受到严格调控，以确保对TGFβ信号的平衡细胞反应。泛素化在调节SMAD稳定性和活性中具有关键作用。已知几种调节SMADs周转的E3泛素连接酶;然而，阻止活性SMADs泛素化或引起活性SMADs去泛素化的蛋白质仍然不确定。在这里，我们证明OTUB 1仅在TGFβ诱导时才被招募到活性磷酸-SMAD 2/3复合物中。此外，OTUB 1在TGFβ介导的基因转录和细胞迁移中具有关键作用。OTUB 1通过与E2泛素缀合酶结合并抑制E2泛素缀合酶来抑制磷酸-SMAD 2/3的泛素化，而不依赖于其催化活性。因此，细胞中OTUB 1的消耗导致TGFβ诱导的磷酸化SMAD 2/3水平的快速丧失，这被蛋白酶体抑制剂硼替佐米挽救。我们的研究结果揭示了OTUB 1在TGFβ通路中的信号诱导磷酸化依赖性募集。 通过SMAD蛋白的TGFβ信号传导控制许多不同的过程，无论是在胚胎发育期间还是在成体组织中。Herhaus等人表明，去泛素化酶OTUB 1通过特异性结合活化的SMAD 2/3复合物并抑制其泛素化来促进TGFβ信号传导。
SMAD transcription factors are key intracellular transducers of TGFβ cytokines. SMADs are tightly regulated to ensure balanced cellular responses to TGFβ signals. Ubiquitylation has a key role in regulating SMAD stability and activity. Several E3 ubiquitin ligases that regulate the turnover of SMADs are known; however, proteins that prevent the ubiquitylation or cause deubiquitylation of active SMADs remain undefined. Here we demonstrate that OTUB1 is recruited to the active phospho-SMAD2/3 complex only on TGFβ induction. Further, OTUB1 has a crucial role in TGFβ-mediated gene transcription and cellular migration. OTUB1 inhibits the ubiquitylation of phospho-SMAD2/3 by binding to and inhibiting the E2 ubiquitin-conjugating enzymes independent of its catalytic activity. Consequently, depletion of OTUB1 in cells causes a rapid loss in levels of TGFβ-induced phospho-SMAD2/3, which is rescued by the proteasomal inhibitor bortezomib. Our findings uncover a signal-induced phosphorylation-dependent recruitment of OTUB1 to its target in the TGFβ pathway. TGFβ signalling through SMAD proteins controls many different processes, both during embryonic development and in adult tissues. Herhaus et al. show that the deubiquitinase OTUB1 promotes TGFβ signalling by binding specifically to activated SMAD2/3 complexes and inhibiting their ubiquitiylation.
登录
查看更多内容
影响因子：
3.5
作者：
Dupont S;Inui M;Newfeld SJ
通讯作者：
Newfeld SJ
影响因子：
64.8
作者：
Lagna, G;Hata, A;Massague, J
通讯作者：
Massague, J
影响因子：
10.5
作者：
Aragon, Eric;Goerner, Nina;Macias, Maria J.
通讯作者：
Macias, Maria J.
影响因子：
4.1
作者：
Kuratomi, G;Komuro, A;Imamura, T
通讯作者：
Imamura, T
影响因子：
4.8
作者：
Bruce, David L.;Macartney, Thomas;Sapkota, Gopal P.
通讯作者：
Sapkota, Gopal P.