title: The SUMO-specific protease SENP5 is required for cell division.
abstract: 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.
authors.affiliation: Department of Pathology, Harvard Medical School, 77 Ave. Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Di Bacco
authors.forename: Jian
authors.initials: J
authors.lastname: Ouyang
authors.forename: Hsiang-Ying
authors.initials: HY
authors.lastname: Lee
authors.forename: Andre
authors.initials: A
authors.lastname: Catic
authors.forename: Hidde
authors.initials: H
authors.lastname: Ploegh
authors.forename: Grace
authors.initials: G
authors.lastname: Gill
mesh_terms: D000818:Animals; D001483:Base Sequence; D020134:Catalytic Domain; D002455:Cell Division / Q000502:physiology*; D002460:Cell Line; D002466:Cell Nucleolus / Q000378:metabolism; D049109:Cell Proliferation; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D025841:Small Ubiquitin-Related Modifier Proteins; D004247:DNA; D003546:Cysteine Endopeptidases