SUMOylation of GTF2IRD1 regulates protein partner interactions and ubiquitin-mediated degradation

• Published in: PloS one 2012-11, Vol.7 (11), p.e49283-e49283
• Main Authors: Widagdo, Jocelyn, Taylor, Kylie M, Gunning, Peter W, Hardeman, Edna C, Palmer, Stephen J
• Format: Article
• Language: English
• Subjects: Amino Acid Motifs; Binding Sites; Biology; Chromosome 7; Cloning; Control stability; Degradation; Deoxyribonucleic acid; DNA; Enzymes; Gene expression; Gene Expression Regulation; Genes; Genomics; Haploinsufficiency; HEK293 Cells; Histone deacetylase; Humans; Ligases; Localization; Lysine; Lysine - chemistry; Lysine - metabolism; Medicine; Molecular Sequence Data; Muscle Proteins - chemistry; Muscle Proteins - metabolism; Muscle Proteins - physiology; Nuclear Proteins - chemistry; Nuclear Proteins - metabolism; Nuclear Proteins - physiology; Plasmids; Post-translation; Proteasomes; Protein binding; Protein Inhibitors of Activated STAT - metabolism; Protein Inhibitors of Activated STAT - physiology; Proteins; Proteolysis; Respiratory distress syndrome; Sequence Alignment; Sequence Analysis, Protein; Signal transduction; SUMO protein; Sumoylation; Trans-Activators - chemistry; Trans-Activators - metabolism; Trans-Activators - physiology; Transcription; Transcription factors; Trends; Two-Hybrid System Techniques; Ubiquitin; Ubiquitin - metabolism; Ubiquitin - physiology; Ubiquitin-Conjugating Enzymes - metabolism; Ubiquitination; Yeast
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0049283

GTF2IRD1 is one of the genes implicated in Williams-Beuren syndrome, a disease caused by haploinsufficiency of certain dosage-sensitive genes within a hemizygous microdeletion of chromosome 7. GTF2IRD1 is a prime candidate for some of the major features of the disease, presumably caused by abnormally reduced abundance of this putative transcriptional repressor protein. GTF2IRD1 has been shown to interact with the E3 SUMO ligase PIASxβ, but the significance of this relationship is largely unexplored. Here, we demonstrate that GTF2IRD1 can be SUMOylated by the SUMO E2 ligase UBC9 and the level of SUMOylation is enhanced by PIASxβ. A major SUMOylation site was mapped to lysine 495 within a conserved SUMO consensus motif. SUMOylation of GTF2IRD1 alters the affinity of the protein for binding partners that contain SUMO-interacting motifs, including a novel family member of the HDAC repressor complex, ZMYM5, and PIASxβ itself. In addition, we show that GTF2IRD1 is targeted for ubiquitination and proteasomal degradation. Cross regulation by SUMOylation modulates this process, thus potentially regulating the level of GTF2IRD1 protein in the cell. These findings, concerning post-translational control over the activity and stability of GTF2IRD1, together with previous work showing how GTF2IRD1 directly regulates its own transcription levels suggest an evolutionary requirement for fine control over GTF2IRD1 activity in the cell.