Phase Separation of <scp>TAF15</scp> C‐Terminal <scp>LC</scp> Domain Enables <scp>RNA</scp> ‐Binding Protein‐Mediated Transcriptional Regulation

TAF15 is an RNA/ssDNA-binding protein and transcriptional activator implicated in diseases such as cancer and ALS. Its C-terminal low-complexity (LC) domain harbors most ALS-associated mutations, suggesting a crucial role in disease mechanisms. Here, we demonstrate that this LC domain mediates dynamic interactions with the RNA-binding protein hnRNPA0, which enhances the transcriptional activity of TAF15. Domain-swapping experiments with the related protein FUS show that the C-terminal LC domain of TAF15 is both necessary and sufficient for hnRNPA0 responsiveness. Phosphomimic mutations in the C-terminal LC domain disrupt this interaction and diminish hnRNPA0-mediated transcriptional activation. hnRNPA0 contains the RNA recognition motif and LC domain, both of which are required for hnRNPA0 to promote transcription. Furthermore, ALS-linked mutations in TAF15 impair its ability to undergo phase separation, reduce binding to hnRNPA0, and eliminate transcriptional enhancement. These findings suggest that TAF15's C-terminal LC domain connects hnRNPA0 to transcriptional regulation, and that this mechanism is disrupted in ALS-associated mutations.