Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.
Department of Cell and Chemical Biology and Oncode Institute, Leiden University Medical Center, 2333 ZC, Leiden, The Netherlands.
Sci Rep. 2020 Sep 24;10(1):15725. doi: 10.1038/s41598-020-72791-0.
Systematic control of the transforming growth factor-β (TGFβ) pathway is essential to keep the amplitude and the intensity of downstream signalling at appropriate levels. Ubiquitination plays a crucial role in the general regulation of this pathway. Here we identify the deubiquitinating enzyme OTUD4 as a transcriptional target of the TGFβ pathway that functions through a positive feedback loop to enhance overall TGFβ activity. Interestingly we demonstrate that OTUD4 functions through both catalytically dependent and independent mechanisms to regulate TGFβ activity. Specifically, we find that OTUD4 enhances TGFβ signalling by promoting the membrane presence of TGFβ receptor I. Furthermore, we demonstrate that OTUD4 inactivates the TGFβ negative regulator SMURF2 suggesting that OTUD4 regulates multiple nodes of the TGFβ pathway to enhance TGFβ activity.
系统控制转化生长因子-β（TGFβ）途径对于保持下游信号的幅度和强度在适当水平至关重要。泛素化在该途径的一般调节中起着关键作用。在这里，我们确定去泛素化酶 OTUD4 是 TGFβ 途径的转录靶标，它通过正反馈环增强整体 TGFβ 活性。有趣的是，我们证明 OTUD4 通过依赖和不依赖催化的机制来调节 TGFβ 活性。具体而言，我们发现 OTUD4 通过促进 TGFβ 受体 I 的膜存在来增强 TGFβ 信号。此外，我们证明 OTUD4 使 TGFβ 负调节剂 SMURF2 失活，表明 OTUD4 通过调节 TGFβ 途径的多个节点来增强 TGFβ 活性。
