DCAF6 reprograms TGF-β responses through TRIM33 destruction

TGF-β signaling plays a pivotal role in regulating numerous cellular processes, primarily through the Smad-dependent pathway. Disruptions of the pathway are associated with developmental disorders and life-threatening diseases, such as cancer. It has been reported that TRIM33 inactivates Smad4 signaling and also drives its own signaling responses. However, the mechanism controlling TRIM33 activity has remained unclear. In this study, we identify DCAF6 as a previously unrecognized ubiquitin ligase for TRIM33. DCAF6 targets TRIM33 at Lys850 for ubiquitin-dependent proteasomal degradation, thus abolishing TRIM33-mediated mono-ubiquitination of Smad4. As such, DCAF6 induces dual consequences: it enhances Smad4-dependent transcriptional and growth inhibitory responses, while simultaneously eliminating TRIM33-dependent developmental responses. Conversely, DCAF6 knockout suppresses Smad4-dependent responses while amplifying TRIM33-dependent responses. Therefore, DCAF6 operates as a critical regulator in the balance of TGF-β signaling between the Smad4 and TRIM33 pathways. These insights deepen our understanding of the dynamics and fate control of TGF-β signaling and may open avenues for therapeutic approaches targeting TGF-β in diseases.