O-GlcNAc Transferase Is Critical for Transducin-like Enhancer of Split ( TLE)-mediated Repression of CanonicalWntSignaling

Background: The molecular mechanisms by which Groucho/TLEs repress canonical Wnt signaling are incompletely understood. Results: OGT interacts with TLEs and facilitates TLE-mediated transcriptional repression. Removal of O-GlcNAc is essential for gene activation from Wnt-responsive promoters. Conclusion: OGT plays a vital role in TLE-mediated repression of Wnt signaling. Significance:O-GlcNAc modification has a profound influence on diverse signaling pathways. The Drosophila Groucho protein and its mammalian orthologues the transducin-like enhancers of split (TLEs) are critical transcriptional corepressors that repress Wnt and other signaling pathways. Although it is known that Groucho/TLEs are recruited to target genes by pathway-specific transcription factors, molecular events after the corepressor recruitment are largely unclear. We report that association of TLEs with O-GlcNAc transferase, an enzyme that catalyzes posttranslational modification of proteins by O-linked N-acetylglucosamine, is essential for TLE-mediated transcriptional repression. Removal of O-GlcNAc from Wnt-responsive gene promoters is critical for gene activation from Wnt-responsive promoters. Thus, these studies identify a molecular mechanism by which Groucho/TLEs repress gene transcription and provide a model whereby O-GlcNAc may control distinct intracellular signaling pathways.