Smad4 sequestered in SFPQ condensates prevents TGF- tumor-suppressive signaling

Loss of TGF-0 growth -inhibitory responses is a hallmark of human cancer. However, the molecular mechanisms underlying the TGF-0 resistance of cancer cells remain to be fully elucidated. Splicing factor prolineand glutamine-rich (SFPQ) is a prion-like RNA -binding protein that is frequently upregulated in human cancers. In this study, we identified SFPQ as a potent suppressor of TGF-0 signaling. The ability of SFPQ to suppress TGF-0 responses depends on its prion-like domain (PrLD) that drives liquid -liquid phase separation (LLPS). Mechanistically, SFPQ physically restrained Smad4 in its condensates, which excluded Smad4 from the Smad complex and chromatin occupancy and thus functionally dampened Smad-dependent transcriptional responses. Accordingly, SFPQ deficiency or loss of phase separation activities rendered human cells hypersensitive to TGF-0 responses. Together, our data identify an important function of SFPQ through LLPS that suppresses Smad transcriptional activation and TGF-0 tumor -suppressive activity.