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Published online 24 March 2003. doi:10.1083/jcb.200212052
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© The Rockefeller University Press, 0021-9525/2003/3/1069 $5.00
The Journal of Cell Biology, Volume 160, Number 7, 1069-1082

Article

The Ulp1 SUMO isopeptidase

: distinct domains required for viability, nuclear envelope localization, and substrate specificity



Shyr-Jiann Li and Mark Hochstrasser

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520

Address correspondence to Mark Hochstrasser, Department of Molecular Biophysics and Biochemistry, Yale University, 266 Whitney Ave., New Haven, CT 06520-8114. Tel.: (203) 432-5101. Fax: (203) 432-5175. E-mail: mark.hochstrasser{at}yale.edu

Protein modification by the ubiquitin-like SUMO protein contributes to many cellular regulatory mechanisms. In Saccharomyces cerevisiae, both sumoylating and desumoylating activities are essential for viability. Of its two known desumoylating enzymes, Ubl-specific protease (Ulp)1 and Ulp2/Smt4, Ulp1 is specifically required for cell cycle progression. A ~200-residue segment, the Ulp domain (UD), is conserved among Ulps and includes a core cysteine protease domain that is even more widespread. Here we demonstrate that the Ulp1 UD by itself can support wild-type growth rates and in vitro can cleave SUMO from substrates. However, in cells expressing only the UD of Ulp1, many SUMO conjugates accumulate to high levels, indicating that the nonessential Ulp1 NH2-terminal domain is important for activity against a substantial fraction of sumoylated targets. The NH2-terminal domain also includes sequences necessary and sufficient to concentrate Ulp1 at nuclear envelope sites. Remarkably, NH2-terminally deleted Ulp1 variants are able, unlike full-length Ulp1, to suppress defects of cells lacking the divergent Ulp2 isopeptidase. Thus, the NH2-terminal regulatory domain of Ulp1 restricts Ulp1 activity toward certain sumoylated proteins while enabling the cleavage of others. These data define key functional elements of Ulp1 and strongly suggest that subcellular localization is a physiologically significant constraint on SUMO isopeptidase specificity.

Key Words: ubiquitin; SUMO; Ulp1; cell cycle; nuclear pore complex

S.-J. Li's present address is Celera SSF, 180 Kimball Way, South San Francisco, CA 94080.

* Abbreviations used in this paper: HU, hydroxyurea; NPC, nuclear pore complex; Ubl, ubiquitin-like protein; UD, Ulp domain; Ulp, Ubl-specific protease.


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