Tankyrase-1-mediated PARsylation directs TFEB partner switching to regulate selective Wnt target gene expression.

Wnt/β-catenin signaling coordinates developmental and oncogenic programs by modulating transcriptional networks. In addition to β-catenin, we previously identified transcription factor EB (TFEB)-a master regulator of lysosomal biogenesis and autophagy-as a Wnt-inducible co-regulator for a subset of Wnt target genes. However, the molecular mechanism underlying this selective transcriptional engagement remained unknown. Here, we show that Wnt3a stimulation promotes TFEB's interaction with TCF-1/LEF-1 without altering lysosomal or autophagy-related gene regulation. This Wnt-specific association requires TFEB's basic helix-loop-helix and leucine zipper domains and coincides with a marked reduction in TFEB-TFEB interaction. Mechanistically, Wnt activation triggers Tankyrase-1-mediated PARsylation of TFEB at K237 and K274 within the basic helix-loop-helix domain, switching its binding preference from homodimers to TCF-1/LEF-1 complexes. PARsylation-deficient TFEB mutants fail to associate with TCF-1/LEF-1 and cannot induce Wnt-TFEB target gene expression. These findings uncover a PARsylation-dependent partner-switching mechanism that reprograms TFEB's transcriptional output under Wnt signaling.