SUMOylation attenuates c-Maf-dependent IL-4 expression

• Published in: European journal of immunology Vol. 40; no. 4; pp. 1174 - 1184
• Main Authors: Lin, Bo-Shiou, Tsai, Pei-Yun, Hsieh, Wan-Yun, Tsao, Hsiao-Wei, Liu, Meng-Wei, Grenningloh, Roland, Wang, Li-Fang, Ho, I. Cheng, Miaw, Shi-Chuen
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley-VCH Verlag 01.04.2010; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Subjects: Amino Acid Sequence; Animals; Cell Line; Cells, Cultured - metabolism; c‐Maf; Humans; Il4 Gene regulation; Interleukin-4 - biosynthesis; Interleukin-4 - genetics; Kidney; Lysine - chemistry; Mice; Molecular Sequence Data; Protein Inhibitors of Activated STAT - chemistry; Protein Inhibitors of Activated STAT - isolation & purification; Protein Inhibitors of Activated STAT - physiology; Protein Interaction Mapping; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-maf - chemistry; Proto-Oncogene Proteins c-maf - physiology; Recombinant Fusion Proteins - physiology; Sequence Alignment; Sequence Homology, Amino Acid; Small Ubiquitin-Related Modifier Proteins - chemistry; Small Ubiquitin-Related Modifier Proteins - genetics; Small Ubiquitin-Related Modifier Proteins - isolation & purification; Small Ubiquitin-Related Modifier Proteins - physiology; SUMOylation; Th2 Cells - metabolism; Transcription, Genetic; Two-Hybrid System Techniques; Ubiquitin-Conjugating Enzymes - chemistry; Ubiquitin-Conjugating Enzymes - physiology
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.200939788

The function of transcription factors can be critically regulated by SUMOylation. c-Maf, the cellular counterpart of v-maf oncogene, is a potent transactivator of the IL-4 gene in Th2 cells. We found in a yeast two-hybrid screen that c-Maf can interact with Ubc9 and PIAS1, two key enzymes of the SUMOylation pathway. In this study, we report that c-Maf co-localized with these two SUMO (small ubiquitin-like modifier) ligases in the nucleus and that c-Maf can be SUMOylated in vitro and also in primary Th2 cells. We also demonstrated that lysine-33 is the dominant, if not the only, SUMO acceptor site of c-Maf. SUMOylation of c-Maf attenuated its transcriptional activity. Reciprocally, a SUMOylation resistant c-Maf was more potent than WT-c-Maf in driving IL-4 production in c-Maf-deficient Th2 cells. Furthermore, we showed that ablation of the SUMO site did not alter the subcellular localization or the stability of c-Maf protein but instead enhanced its recruitment to the Il4-promoter. We conclude that SUMOylation at lysine-33 is a functionally critical post-translational modification event of c-Maf in Th cells.