MEL-18 interacts with HSF2 and the SUMO E2 UBC9 to inhibit HSF2 sumoylation.
In a previous study we found that sumoylation of the DNA-binding protein heat shock factor 2 (HSF2) is up-regulated during mitosis, but the mechanism that mediates this regulation was unknown. Here we show that HSF2 interacts with the polycomb protein MEL-18, that this interaction decreases during mitosis, and that overexpression and RNA interference-mediated reduction of MEL-18 result in decreased and increased HSF2 sumoylation, respectively. Other results suggest that MEL-18 may also function to inhibit the sumoylation of other cellular proteins. The results also show that MEL-18 is able to interact with the small ubiquitin-like modifier (SUMO) ubiquitin carrier protein (E2) enzyme UBC9 and that MEL-18 inhibits the ability of UBC9 to transfer the SUMO protein to target proteins. Together, the results in this work suggest a mechanism in which MEL-18 bound to HSF2 inhibits its sumoylation by binding to and inhibiting the activity of UBC9 enzymes in the vicinity of HSF2. These results provide an explanation for how mitotic HSF2 sumoylation is regulated and suggest that MEL-18, in contrast to the sumoylation-stimulating activities of the polycomb protein PC2, actually functions like an anti-SUMO ubiquitin-protein isopeptide ligase (E3), interacting both with HSF2 and the SUMO E2 UBC9 but acting to inhibit UBC9 activity to decrease sumoylation of a target protein, in this case that of HSF2.
Zhang
Jie
J
Department of Molecular and Cellular Biochemistry, Chandler Medical Center, University of Kentucky, Lexington, Kentucky 40536, USA.
Goodson
Michael L
ML
Hong
Yiling
Y
Sarge
Kevin D
KD
D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008025:Ligases; D008938:Mitosis / Q000502:physiology*; D063150:Polycomb Repressive Complex 1; D063146:Polycomb-Group Proteins; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D000098843:Ubiquitin-Conjugating Enzyme UBC9
D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; C489348:PCGF2 protein, human; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D025842:SUMO-1 Protein; D014157:Transcription Factors; C070389:HSF2 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D063150:Polycomb Repressive Complex 1; D044767:Ubiquitin-Protein Ligases; D008025:Ligases; C570427:CBX4 protein, human; D000098843:Ubiquitin-Conjugating Enzyme UBC9