BBB seminar: Frauke Melchior
Regulation of SUMOylation by reversible oxidation of SUMO conjugating enzymes
Department of Biochemistry I, University of Göttingen, Germany
Small ubiquitin related modifier SUMO-1 and its homologs can be reversibly conjugated to a large number of cellular proteins. Depending on the specific target, SUMOylation serves to regulate protein-protein and protein-DNA interactions, intracellular localization and may protect from ubiquitin-dependent degradation. SUMOylation involves an enzymatic cascade that resembles ubiquitination, and the modification can be reverted by isopeptidases. The E1 activating enzyme (Aos1/Uba2) and the E2 conjugating enzyme (Ubc9) are sufficient for modification of some targets in vitro, others require E3 ligases. While SUMOylation has emerged as an important regulatory mechanism of protein function, little is known about the regulation of sumoylation itself. It has been reported that it is increased following exposure to various stresses including strong oxidative stress. Conversely, we report that ROS (Reactive Oxygen Species), at low concentrations, result in the rapid disappearance of most SUMO conjugates including those of key transcription factors. This is due to direct and reversible inhibition of SUMO conjugating enzymes through the formation of (a) disulfide bond(s) involving the catalytic cysteines of the SUMO E1 subunit Uba2 and the E2-conjugating enzyme Ubc9. The same phenomenon is also observed in a physiological scenario of endogenous ROS production, the respiratory burst in macrophages. Thus, our findings add SUMO conjugating enzymes to the small list of specific direct effectors of H2O2 and implicate ROS as key regulators of the sumoylation-desumoylation equilibrium.
1. Mahajan, R., Delphin, C., Guan, T., Gerace, L. and Melchior, F. (1997) Cell 88, 97-107
2. Pichler, A., Gast, A., Seeler, J.S., Dejean, A. and Melchior, F. (2002) Cell 108, 109-120
3. Pichler, A, Knipscheer, P., Oberhofer, E., van Dijk, W.J., Körner, R., Olsen, J.V., Jentsch, S., Melchior, F. and Sixma, T.K. (2005) Nat. Struct. & Mol. Biol.12, 264-269
4. Bossis, G., and Melchior, F. (2006) Mol Cell, 21, 349-357
Host: Anni Vedeler, Department of Biomedicine
The research of Prof. Frauke Melchior, Head of the Department of Biochemistry I at the University of Göttingen, Germany, centers around posttranslational modification with small ubiquitin-related proteins of the SUMO family. Attachment of SUMO serves to regulate protein-protein interactions, subcellular localization, enzymatic activity, and in some cases protects proteins from ubiquitin-dependent degradation.
Projects in her lab aim to understand mechanism, regulation and function of SUMOylation, with special interest in the connection between SUMOylation and nucleocytoplasmic transport, the function and regulation of the SUMO model target RanGAP1, and links between SUMO- and ubiquitin-conjugation pathways.