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Molecular and Cellular Biology, December 2008, p. 7476-7486, Vol. 28, No. 24
0270-7306/08/$08.00+0     doi:10.1128/MCB.00103-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Decreased Recognition of SUMO-Sensitive Target Genes following Modification of SF-1 (NR5A1){triangledown} ,{ddagger}

Lioudmila A. Campbell,1,3,{dagger} Emily J. Faivre,1,{dagger} Matthew D. Show,1 Jared G. Ingraham,1 Jeremy Flinders,2 John D. Gross,2 and Holly A. Ingraham1*

Department of Cellular and Molecular Pharmacology and Physiology,1 Department of Pharmaceutical Chemistry,2 Graduate Program in Biological Sciences, 1550 4th Street, Rock Hall, Mission Bay Campus, University of California, San Francisco, Box 0444, San Francisco, California 94143-26113

Received 18 January 2008/ Returned for modification 26 February 2008/ Accepted 19 September 2008

SUMO modification of nuclear receptors, including the constitutively active receptor steroidogenic factor 1 (SF-1; NR5A1), is proposed to repress their transcriptional activity. We examined the functional and structural consequences of SF-1 sumoylation at two conserved lysines (Lys119 and Lys194) that reside adjacent to the DNA-binding domain (DBD) and ligand-binding domain (LBD), respectively. Surprisingly, while previous loss-of-function studies predicted that sumoylation at Lys194 would greatly impact SF-1 function, the conformation and coregulator recruitment of fully sumoylated SF-1 LBD protein was either unchanged or modestly impaired. Sumoylation at Lys194 also modestly reduced Ser203 phosphorylation. In contrast to these findings, sumoylation of the DBD at Lys119 resulted in a marked and selective loss of DNA binding to noncanonical SF-1 targets, such as inhibin{alpha}; this binding deficit was extended to all sites when the sumoylated human mutant (R92Q) protein, which exhibits lower activity, was used. Consistent with this result, the K119R mutant, compared to wild-type SF-1, was selectively recruited to a "SUMO-sensitive" site in the endogenous inhibin{alpha} promoter, leading to increased transcription. DNA binding and sumoylation of Lys119 appeared to be mutually exclusive, suggesting that once SF-1 is bound to DNA, sumoylation may be less important in regulating SF-1 activity. We propose that sumoylation of nuclear receptors imposes an active posttranslational mark that dampens recognition of SUMO-sensitive target genes to restrain their expression.

* Corresponding author. Mailing address: Department of Cellular and Molecular Pharmacology and Physiology, 1550 4th Street, Rock Hall, Mission Bay Campus, University of California, San Francisco, Box 0444, San Francisco, CA 94143-2611. Phone: (415) 476-2731. Fax: (415) 514-4459. E-mail: holly.ingraham{at}ucsf.edu

{triangledown} Published ahead of print on 6 October 2008.

{ddagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{dagger} L.A.C. and E.J.F. contributed equally to this study.

Molecular and Cellular Biology, December 2008, p. 7476-7486, Vol. 28, No. 24
0270-7306/08/$08.00+0     doi:10.1128/MCB.00103-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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