TIF1γ Protein Regulates Epithelial-Mesenchymal Transition by Operating as a Small Ubiquitin-like Modifier (SUMO) E3 Ligase for the Transcriptional Regulator SnoN1

Epithelial-mesenchymal transition (EMT) is a fundamental cellular process that contributes to epithelial tissue morphogenesis during normal development and in tumor invasiveness and metastasis. The transcriptional regulator SnoN robustly influences EMT in response to the cytokine TGF beta, but the mechanisms that regulate the fundamental role of SnoN in TGF beta-induced EMT are not completely understood. Here we employ interaction proteomics to uncover the signaling protein TIF1 gamma as a specific interactor of SnoN1 but not the closely related isoform SnoN2. A 16-amino acid peptide within a unique region of SnoN1 mediates the interaction of SnoN1 with TIF1 gamma. Strikingly, although TIF1 gamma is thought to act as a ubiquitin E3 ligase, we find that TIF1 gamma operates as a small ubiquitin-like modifier (SUMO) E3 ligase that promotes the sumoylation of SnoN1 at distinct lysine residues. Importantly, TIF1 gamma -induced sumoylation is required for the ability of SnoN1 to suppress TGF beta-induced EMT, as assayed by the disruption of the morphogenesis of acini in a physiologically relevant three-dimensional model of normal murine mammary gland (NMuMG) epithelial cells. Collectively, our findings define a novel TIF1 gamma-SnoN1 sumoylation pathway that plays a critical role in EMT and has important implications for our understanding of TGF beta signaling and diverse biological processes in normal development and cancer biology.