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Molecular and Cellular Biology, June 2006, p. 4489-4498, Vol. 26, No. 12
0270-7306/06/$08.00+0     doi:10.1128/MCB.02301-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The SUMO-Specific Protease SENP5 Is Required for Cell Division

Alessandra Di Bacco,1 Jian Ouyang,1 Hsiang-Ying Lee,1 Andre Catic,2 Hidde Ploegh,2 and Grace Gill1*

Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115,1 Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 021422

Received 1 December 2005/ Returned for modification 11 January 2006/ Accepted 28 March 2006

Posttranslational modification of substrates by the small ubiquitin-like modifier, SUMO, regulates diverse biological processes, including transcription, DNA repair, nucleocytoplasmic trafficking, and chromosome segregation. SUMOylation is reversible, and several mammalian homologs of the yeast SUMO-specific protease Ulp1, termed SENPs, have been identified. We demonstrate here that SENP5, a previously uncharacterized Ulp1 homolog, has SUMO C-terminal hydrolase and SUMO isopeptidase activities. In contrast to other SENPs, the C-terminal catalytic domain of SENP5 preferentially processed SUMO-3 compared to SUMO-1 precursors and preferentially removed SUMO-2 and SUMO-3 from SUMO-modified RanGAP1 in vitro. In cotransfection assays, SENP5 preferentially reduced high-molecular-weight conjugates of SUMO-2 compared to SUMO-1 in vivo. Full-length SENP5 localized to the nucleolus. Deletion of the noncatalytic N-terminal domain led to loss of nucleolar localization and increased de-SUMOylation activity in vivo. Knockdown of SENP5 by RNA interference resulted in increased levels of SUMO-1 and SUMO-2/3 conjugates, inhibition of cell proliferation, defects in nuclear morphology, and appearance of binucleate cells, revealing an essential role for SENP5 in mitosis and/or cytokinesis. These findings establish SENP5 as a SUMO-specific protease required for cell division and suggest that mechanisms involving both the catalytic and noncatalytic domains determine the distinct substrate specificities of the mammalian SUMO-specific proteases.

* Corresponding author. Mailing address: Department of Pathology, Harvard Medical School, 77 Ave. Louis Pasteur, Boston, MA 02115. Phone: (617) 432-0985. Fax: (617) 432-6225. E-mail: grace_gill{at}hms.harvard.edu.

Molecular and Cellular Biology, June 2006, p. 4489-4498, Vol. 26, No. 12
0270-7306/06/$08.00+0     doi:10.1128/MCB.02301-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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