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J. Biol. Chem., Vol. 283, Issue 12, 7464-7469, March 21, 2008

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MEL-18 Interacts with HSF2 and the SUMO E2 UBC9 to Inhibit HSF2 Sumoylation^*

From the Department of Molecular and Cellular Biochemistry, Chandler Medical Center, University of Kentucky, Lexington, Kentucky 40536

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.

Received for publication, August 24, 2007 , and in revised form, January 11, 2008.

^* This work was supported by National Institutes of Health Grants GM61053 and GM64606 (to K. D. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Section of Microbiology, University of California, Davis, CA 95616.

² Present address: Dept. of Biology, University of Dayton, Dayton, OH 45469.

³ To whom correspondence should be addressed. E-mail: kdsarge{at}uky.edu.

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