DCAF6 reprograms TGF-β responses through TRIM33 destruction.

DCAF6 is identified as a ubiquitin ligase that targets TRIM33 at Lys850 for proteasomal degradation, abolishing TRIM33-mediated mono-ubiquitination of Smad4.

• Why it matters: TGF-β signaling controls key cellular processes, and misregulation contributes to developmental disorders and cancer; the mechanism governing TRIM33 activity was unclear.
• What they did: The study identifies DCAF6 as a TRIM33 ubiquitin ligase and shows it promotes Lys850 ubiquitin-dependent proteasomal degradation, removing TRIM33 effects on Smad4.
• The result: DCAF6 enhances Smad4-dependent transcriptional and growth inhibitory responses while eliminating TRIM33-dependent developmental responses; DCAF6 knockout suppresses Smad4 responses and amplifies TRIM33-dependent responses.