OTUD4 enhances TGF beta signalling through regulation of the TGF beta receptor complex

Systematic control of the transforming growth factor-beta (TGF beta) 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 TGF beta pathway that functions through a positive feedback loop to enhance overall TGF beta activity. Interestingly we demonstrate that OTUD4 functions through both catalytically dependent and independent mechanisms to regulate TGF beta activity. Specifically, we find that OTUD4 enhances TGF beta signalling by promoting the membrane presence of TGF beta receptor I. Furthermore, we demonstrate that OTUD4 inactivates the TGF beta negative regulator SMURF2 suggesting that OTUD4 regulates multiple nodes of the TGF beta pathway to enhance TGF beta activity.