SUMOylation and De-SUMOylation: Wrestling with Life's Processes

The small ubiquitin-like modifier (SUMO) is a ubiquitin-like protein that covalently modifies a large number of cellular proteins. SUMO modification has emerged as an important regulatory mechanism for protein function and localization. SUMOylation is a dynamic process that is mediated by activating (E1), conjugating (E2), and ligating (E3) enzymes and readily reversed by a family of ubiquitin-like protein-specific proteases (Ulp) in yeast and sentrin/SUMO-specific proteases (SENP) in human. This review will focus on the de-SUMOylating enzymes with special attention to their biological function. The small ubiquitin-like modifier (SUMO) is a ubiquitin-like protein that covalently modifies a large number of cellular proteins. SUMO modification has emerged as an important regulatory mechanism for protein function and localization. SUMOylation is a dynamic process that is mediated by activating (E1), conjugating (E2), and ligating (E3) enzymes and readily reversed by a family of ubiquitin-like protein-specific proteases (Ulp) in yeast and sentrin/SUMO-specific proteases (SENP) in human. This review will focus on the de-SUMOylating enzymes with special attention to their biological function. Many biochemical pathways are reversible to create an on and off state that is essential for biological regulation. A reversible system allows for quick termination of a biological response that has to be precisely controlled. The SUMO 2The abbreviations used are: SUMO, small ubiquitin-like modifier; SENP, sentrin/SUMO-specific protease; siRNA, small interfering RNA; TNF, tumor necrosis factor; Epo, erythropoietin; VHL, von Hippel-Lindau. modification pathway is an example of a reversible system that is controlled by a series of on and off enzymes (Fig. 1) (1Yeh E.T. Gong L. Kamitani T. Gene (Amst.). 2000; 248: 1-14Crossref PubMed Scopus (420) Google Scholar). In contrast to the much more complex ubiquitin pathway (2Hershko A. Ciechanover A. Varshavsky A. Nat. Med. 2000; 6: 1073-1081Crossref PubMed Scopus (572) Google Scholar), SUMOylation utilizes only a single conjugating enzyme, Ubc9 (3Gong L. Kamitani T. Fujise K. Caskey L.S. Yeh E.T. J. Biol. Chem. 1997; 272: 28198-28201Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar), and a limited number of ligases (4Johnson E.S. Gupta A.A. Cell. 2001; 106: 735-744Abstract Full Text Full Text PDF PubMed Scopus (529) Google Scholar, 5Pichler A. Gast A. Seeler J.S. Dejean A. Melchior F. Cell. 2002; 108: 109-120Abstract Full Text Full Text PDF PubMed Scopus (645) Google Scholar, 6Kahyo T. Nishida T. Yasuda H. Mol. Cell. 2001; 8: 713-718Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar). This simplicity also manifests in the off step because there are only two SUMO-deconjugating enzymes in yeast and six in human. One may assume that these limited numbers of on and off enzymes would sufficient to regulate only be a small number of substrates and biological pathways. However, the number of SUMO substrates continues to expand, and the varieties of systems that are known to be regulated by SUMO also proliferate quickly. Here, I will review only the enzymes that are involved in the de-SUMOylation pathways to provide insights into how these limited numbers of proteases are able to regulate a diverse array of biological responses. SUMO-specific proteases are C48 cysteine proteases that possess a conserved catalytic domain characterized by the catalytic triad (histidine, aspartate, and cysteine) and a conserved glutamine residue required for the formation of the oxyanion hole in the active site (7Li S.J. Hochstrasser M. Nature. 1999; 398: 246-251Crossref PubMed Scopus (608) Google Scholar). Members of the C48 cysteine protease family have N- and C-terminal sequences that differ from each other. Homologs of these proteases are present in plant, yeast, and mammalian cells. In this review, I will focus on the two yeast ubiquitin-like protein-specific proteases (Ulp) and the six human sentrin/SUMO-specific proteases (SENP) (Table 1).TABLE 1Human SENPsHuman SENPs (1Yeh E.T. Gong L. Kamitani T. Gene (Amst.). 2000; 248: 1-14Crossref PubMed Scopus (420) Google Scholar)Other namesPrimary locationSpecificityEnzymatic activitySENP1SuPr-2Nucleoplasm (11Gong L. Millas S. Maul G.G. Yeh E.T. J. Biol. Chem. 2000; 275: 3355-3359Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar)SUMO1/2/3 (11Gong L. Millas S. Maul G.G. Yeh E.T. J. Biol. Chem. 2000; 275: 3355-3359Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar)C-terminal hydrolase, isopeptidase (11Gong L. Millas S. Maul G.G. Yeh E.T. J. Biol. Chem. 2000; 275: 3355-3359Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar)SENP2SuPr-1, AXAM2, SMT3IP2Nuclear pore, nuclear speckle (16Hang J. Dasso M. J. Biol. Chem. 2002; 277: 19961-19966Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar, 17Zhang H. Saitoh H. Matunis M.J. Mol. Cell. Biol. 2002; 22: 6498-6508Crossref PubMed Scopus (229) Google Scholar, 18Cheng J. Bawa T. Lee P. Gong L. Yeh E.T. Neoplasia (N. Y.). 2006; 8: 667-676Crossref PubMed Scopus (185) Google Scholar)SUMO1/2/3 (16Hang J. Dasso M. J. Biol. Chem. 2002; 277: 19961-19966Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar, 17Zhang H. Saitoh H. Matunis M.J. Mol. Cell. Biol. 2002; 22: 6498-6508Crossref PubMed Scopus (229) Google Scholar)C-terminal hydrolase, isopeptidase (16Hang J. Dasso M. J. Biol. Chem. 2002; 277: 19961-19966Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar, 17Zhang H. Saitoh H. Matunis M.J. Mol. Cell. Biol. 2002; 22: 6498-6508Crossref PubMed Scopus (229) Google Scholar)SENP3SSP3, SMT3IP1Nucleolus (19Nishida T. Tanaka H. Yasuda H. Eur. J. Biochem. 2000; 267: 6423-6427Crossref PubMed Scopus (143) Google Scholar, 20Gong L. Yeh E.T. J. Biol. Chem. 2006; 281: 15869-15877Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar, 21Di Bacco A. Ouyang J. Lee H.Y. Catic A. Ploegh H. Gill G. Mol. Cell. Biol. 2006; 26: 4489-4498Crossref PubMed Scopus (143) Google Scholar)SUMO2/3 (20Gong L. Yeh E.T. J. Biol. Chem. 2006; 281: 15869-15877Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar, 21Di Bacco A. Ouyang J. Lee H.Y. Catic A. Ploegh H. Gill G. Mol. Cell. Biol. 2006; 26: 4489-4498Crossref PubMed Scopus (143) Google Scholar)Isopeptidase (19Nishida T. Tanaka H. Yasuda H. Eur. J. Biochem. 2000; 267: 6423-6427Crossref PubMed Scopus (143) Google Scholar, 20Gong L. Yeh E.T. J. Biol. Chem. 2006; 281: 15869-15877Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar, 21Di Bacco A. Ouyang J. Lee H.Y. Catic A. Ploegh H. Gill G. Mol. Cell. Biol. 2006; 26: 4489-4498Crossref PubMed Scopus (143) Google Scholar)SENP5Nucleolus (20Gong L. Yeh E.T. J. Biol. Chem. 2006; 281: 15869-15877Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar, 21Di Bacco A. Ouyang J. Lee H.Y. Catic A. Ploegh H. Gill G. Mol. Cell. Biol. 2006; 26: 4489-4498Crossref PubMed Scopus (143) Google Scholar)SUMO2/3 (20Gong L. Yeh E.T. J. Biol. Chem. 2006; 281: 15869-15877Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar, 21Di Bacco A. Ouyang J. Lee H.Y. Catic A. Ploegh H. Gill G. Mol. Cell. Biol. 2006; 26: 4489-4498Crossref PubMed Scopus (143) Google Scholar)Isopeptidase (20Gong L. Yeh E.T. J. Biol. Chem. 2006; 281: 15869-15877Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar, 21Di Bacco A. Ouyang J. Lee H.Y. Catic A. Ploegh H. Gill G. Mol. Cell. Biol. 2006; 26: 4489-4498Crossref PubMed Scopus (143) Google Scholar)SENP6SUSP1, SSP1Nucleoplasm (18Cheng J. Bawa T. Lee P. Gong L. Yeh E.T. Neoplasia (N. Y.). 2006; 8: 667-676Crossref PubMed Scopus (185) Google Scholar, 23Mukhopadhyay D. Ayaydin F. Kolli N. Tan S.H. Anan T. Kametaka A. Azuma Y. Wilkinson K.D. Dasso M. J. Cell Biol. 2006; 174: 939-949Crossref PubMed Scopus (126) Google Scholar)SUMO2/3 (23Mukhopadhyay D. Ayaydin F. Kolli N. Tan S.H. Anan T. Kametaka A. Azuma Y. Wilkinson K.D. Dasso M. J. Cell Biol. 2006; 174: 939-949Crossref PubMed Scopus (126) Google Scholar)Chain editing (23Mukhopadhyay D. Ayaydin F. Kolli N. Tan S.H. Anan T. Kametaka A. Azuma Y. Wilkinson K.D. Dasso M. J. Cell Biol. 2006; 174: 939-949Crossref PubMed Scopus (126) Google Scholar)SENP7Nucleoplasm (18Cheng J. Bawa T. Lee P. Gong L. Yeh E.T. Neoplasia (N. Y.). 2006; 8: 667-676Crossref PubMed Scopus (185) Google Scholar)?SUMO2/3?Chain editing Open table in a new tab Yeast has a single SUMO-like modifier, Smt3, and two Smt3-specific proteases, Ulp1 and Ulp2. Both Smt3 and Ulp2 (Smt4) were identified from the same screen as suppressors of the Mif2 (a centromeric protein) mutation (8Meluh P.B. Koshland D. Mol. Biol. Cell. 1995; 6: 793-807Crossref PubMed Scopus (354) Google Scholar). Ulp1 is a protein of 621 amino acids that contains the catalytic domain at the C terminus and an N-terminal domain that attaches this protease to the nuclear pore (7Li S.J. Hochstrasser M. Nature. 1999; 398: 246-251Crossref PubMed Scopus (608) Google Scholar). Ulp1 possesses the C-terminal hydrolase activity required for removing C-terminal amino acids from Smt3 to reveal the diglycine residues important for conjugation to Smt3 substrates. Ulp1 also has the isopeptidase activity that is essential for removing Smt3 from conjugated substrates. Ulp2 (Smt4) is a 1034-amino acid protease that possesses only isopeptidase activity (9Li S.J. Hochstrasser M. Mol. Cell. Biol. 2000; 20: 2367-2377Crossref PubMed Scopus (312) Google Scholar). It is localized in the nucleoplasm. Yeast deficient in Ulp2 accumulates Smt3 polymers, suggesting that Ulp2 is also involved in the processing of the Smt3 chains (10Bylebyl G.R. Belichenko I. Johnson E.S. J. Biol. Chem. 2003; 278: 44113-44120Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar). The SENPs can be divided into three families. The first family consists of SENP1 and SENP2, which have broad specificity for the three mammalian SUMOs (SUMO1–3). The second family includes SENP3 and SENP5, which favor SUMO2/3 as substrates and are localized in the nucleolus. The third family contains SENP6 and SENP7, which have an additional loop inserted in the catalytic domain and also appear to prefer SUMO2/3. From an evolutionary standpoint, SENP1–3 and SENP5 are more closely related to Ulp1, whereas SENP6 and SENP7 are related to Ulp2. SENP1 is localized in the nucleoplasm but not in the nucleolus (11Gong L. Millas S. Maul G.G. Yeh E.T. J. Biol. Chem. 2000; 275: 3355-3359Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar). It contains a nuclear localization signal in the N terminus (12Bailey D. O’Hare P. J. Biol. Chem. 2004; 279: 692-703Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar) and a nuclear export sequence near the C terminus (13Kim Y.H. Sung K.S. Lee S.J. Kim Y.O. Choi C.Y. Kim Y. FEBS Lett. 2005; 579: 6272-6278Crossref PubMed Scopus (42) Google Scholar). In the SENP1–/– embryo, the SUMO1 precursor cannot be processed, suggesting that SENP1 is the main SUMO1 C-terminal hydrolase (14Cheng J. Kang X. Zhang S. Yeh E.T. Cell. 2007; 131: 584-595Abstract Full Text Full Text PDF PubMed Scopus (499) Google Scholar). However, SENP1 is an efficient isopeptidase for all SUMOs. SENP2 also possesses nuclear localization and export signals (15Itahana Y. Yeh E.T. Zhang Y. Mol. Cell. Biol. 2006; 26: 4675-4689Crossref PubMed Scopus (79) Google Scholar). When exported from the nucleus, it is quickly ubiquitinated and degraded. SENP2 was reported to be tethered to the nuclear pore through binding to Nup153 nucleoporin (16Hang J. Dasso M. J. Biol. Chem. 2002; 277: 19961-19966Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar, 17Zhang H. Saitoh H. Matunis M.J. Mol. Cell. Biol. 2002; 22: 6498-6508Crossref PubMed Scopus (229) Google Scholar). Furthermore, SENP2 is also localized in a yet undefined nuclear speckle that is distinct from the nuclear body (18Cheng J. Bawa T. Lee P. Gong L. Yeh E.T. Neoplasia (N. Y.). 2006; 8: 667-676Crossref PubMed Scopus (185) Google Scholar). SENP2 has isopeptidase activity for all SUMOs. SENP3 and SENP5 are both localized predominately in the nucleolus (19Nishida T. Tanaka H. Yasuda H. Eur. J. Biochem. 2000; 267: 6423-6427Crossref PubMed Scopus (143) Google Scholar, 20Gong L. Yeh E.T. J. Biol. Chem. 2006; 281: 15869-15877Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar, 21Di Bacco A. Ouyang J. Lee H.Y. Catic A. Ploegh H. Gill G. Mol. Cell. Biol. 2006; 26: 4489-4498Crossref PubMed Scopus (143) Google Scholar). The nucleolar localization signals are positioned in their N termini. Both SENP3 and SENP5 show preference for SUMO2/3. SENP6 has a distinct split of its catalytic domain by an insertion (22Kim K.I. Baek S.H. Jeon Y.J. Nishimori S. Suzuki T. S. N. Saitoh H. Tanaka K. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). It was to be localized to the in and (22Kim K.I. Baek S.H. Jeon Y.J. Nishimori S. Suzuki T. S. N. Saitoh H. Tanaka K. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). However, from that SENP6 is localized in the nucleoplasm (18Cheng J. Bawa T. Lee P. Gong L. Yeh E.T. Neoplasia (N. Y.). 2006; 8: 667-676Crossref PubMed Scopus (185) Google Scholar, 23Mukhopadhyay D. Ayaydin F. Kolli N. Tan S.H. Anan T. Kametaka A. Azuma Y. Wilkinson K.D. Dasso M. J. Cell Biol. 2006; 174: 939-949Crossref PubMed Scopus (126) Google Scholar). SENP6 also to prefer SUMO2/3 as substrates (23Mukhopadhyay D. Ayaydin F. Kolli N. Tan S.H. Anan T. Kametaka A. Azuma Y. Wilkinson K.D. Dasso M. J. Cell Biol. 2006; 174: 939-949Crossref PubMed Scopus (126) Google Scholar). SENP7 is the characterized that is localized in the nucleoplasm (18Cheng J. Bawa T. Lee P. Gong L. Yeh E.T. Neoplasia (N. Y.). 2006; 8: 667-676Crossref PubMed Scopus (185) Google Scholar). However, its catalytic activity has not of the and that Ulp1 to the cysteine protease Mol. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). The of Ulp1 possesses and and with cysteine proteases in the active site that includes the and three and the catalytic The Ulp1 and Smt3 is and includes the of Smt3 and an of the The of Smt3 through a the active site The Ulp1 active site cysteine protease active in that the is by and by and the oxyanion hole is by and The of that its active site and cysteine proteases D. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). Furthermore, the of SENP2 and that SENP2 binding to a in the complex that the and from In and all their to to with the SUMO1 The is to that of that SENP2 SUMO1 This C-terminal hydrolase activity is on the C-terminal of these SUMOs. However, SENP2 from Furthermore, the isopeptidase activity of SENP2 is its C-terminal hydrolase suggesting that SENP2 more readily with SUMO with SUMO into the of isopeptidase activity from the of in complex with a of L. A. Nat. Mol. Biol. 2006; PubMed Scopus Google Scholar). It that there is a and of by The binding the conserved C-terminal of SUMO1 and the main of SENP1 the Furthermore, the of a and When the SUMO1 precursor to SENP1 is the has the of the to the in on these it was that an SUMO SUMO and SENP1 the of the of the of the of the of the of SENP2 in complex with SUMO also a to the that C-terminal amino acid residues the the SENP2 D. Nat. Mol. Biol. 2006; PubMed Scopus Google Scholar). This to be for processing of SUMO The is on the the catalytic domain of SENP1 SENP2 and SUMO The provide insights binding and the catalytic However, these not for the of the N of the SENPs to a function as both the C-terminal hydrolase and isopeptidase for Smt3 (7Li S.J. Hochstrasser M. Nature. 1999; 398: 246-251Crossref PubMed Scopus (608) Google Scholar). The isopeptidase activity of Ulp1 is essential for of yeast at the The catalytic domain of Ulp1 is sufficient to the of Ulp1 in yeast S.J. Hochstrasser M. J. Cell Biol. 2003; PubMed Scopus Google Scholar). In Ulp1 is not essential for but Ulp1 nuclear and are more to A. J. Cell 2002; Google Scholar). This nuclear is on the isopeptidase activity because it is not by the of of Furthermore, Ulp1 a of localization. the and Ulp1 is localized at the nuclear However, Ulp1 is localized in the The of cellular Ulp1 is not with but with three and T. Nat. Cell Biol. 2003; PubMed Scopus Google Scholar). of the catalytic domain of Ulp1 in the the mechanism of this is In two and which to the of the nuclear pore are required to Ulp1 to the nuclear X. C.Y. G. J. Cell Biol. 2004; PubMed Scopus Google Scholar). of the in and In a a nuclear protein not with the nuclear pore was to be required for of the nuclear and for nuclear pore complex localization of Ulp1 A. Hochstrasser M. J. Cell Biol. 2007; PubMed Scopus (79) Google Scholar). Both and Ulp1 to in the and to (9Li S.J. Hochstrasser M. Mol. Cell. Biol. 2000; 20: 2367-2377Crossref PubMed Scopus (312) Google Scholar). Ulp2 was to at centromeric and through of the function of J. A. Y. N. S.J. Mol. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). to Smt3 modification the Ulp2 suggesting that is a a of required for centromeric it was that Ulp2 is required for of but is not required for Hochstrasser M. Mol. Cell. Biol. 2007; PubMed Scopus Google Scholar). of SENP1 that it is active both and in (11Gong L. Millas S. Maul G.G. Yeh E.T. J. Biol. Chem. 2000; 275: 3355-3359Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar). However, SENP1 only but not in The of SENP1 on these two substrates in was to the nuclear localization of SENP1 is not able to regulate which is localized to the of the nuclear pore This is an because SENP1 can the and through a nuclear localization signal and nuclear export sequence (12Bailey D. O’Hare P. J. Biol. Chem. 2004; 279: 692-703Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar, Y.H. Sung K.S. Lee S.J. Kim Y.O. Choi C.Y. Kim Y. FEBS Lett. 2005; 579: 6272-6278Crossref PubMed Scopus (42) Google Scholar). the and its are H. S. A. 2000; PubMed Scopus Google Scholar, 2002; PubMed Scopus Google Scholar), the system is an to the of SENPs in the of a complex biological In a that SENP1 is the of J. D. Yeh E.T. Mol. Cell. Biol. 2004; PubMed Scopus Google Scholar). SENP1 1) to its to This is because SENP1 is in an and but not in (18Cheng J. Bawa T. Lee P. Gong L. Yeh E.T. Neoplasia (N. Y.). 2006; 8: 667-676Crossref PubMed Scopus (185) Google Scholar). Furthermore, the SENP1 by binding to an in the SENP1 T. J. Yeh E.T. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). the of SENP1 in the of SENP1 that were by an (18Cheng J. Bawa T. Lee P. Gong L. Yeh E.T. Neoplasia (N. Y.). 2006; 8: 667-676Crossref PubMed Scopus (185) Google Scholar). that of SENP1 in the to of a at which in SENP1 is the first to a in in human. In to SENP1 also a to SUMOylation of its and SENP1 the activity of Y. J. N. Zhang X. K. Nat. Cell Biol. 2007; PubMed Scopus Google Scholar). Furthermore, as and the of with SENP1 by SENP1 a in through de-SUMOylation of which of the In it was that SENP1 can be in the by and that the of SENP1 from through a mechanism X. Y. L. Y. D. Zhang H. Y. Kim Y.O. Kim Y. S. Cell PubMed Scopus Google Scholar). nuclear of SENP1 with de-SUMOylation of protein 1) and of to an in it is that SENP1 can through SENP1 also by de-SUMOylating domain 1) of the of on J. Yeh E.T. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). This activity may also to the of Many of the reported were on of SENP1 in SENP1 by important to reveal the of SENP1 is through the in A insertion the first the SENP1 to a in the of SENP1 and at T. P. M. A. S. Mol. Cell. Biol. 2005; PubMed Scopus Google Scholar). It was that this mutation an in SUMO1 but not SUMO2/3 The was to that are with has SENP1 a that of the SENP1 in in as a of from deficient (14Cheng J. Kang X. Zhang S. Yeh E.T. Cell. 2007; 131: 584-595Abstract Full Text Full Text PDF PubMed Scopus (499) Google Scholar). SENP1 by the of is at two residues by a family of enzymes hydrolase is important for to to its ubiquitin the to and It was that is and to to the complex and to that SUMOylation of which allows it to to the protein in a also to and SENP1 SUMOylation of binding to the and reveal that SUMO can also as a signal for protein SENP1 a in as Epo, and it has the to regulate and the is an of SENP2 that has to to the nuclear body S. S. A. P. P.B. Mol. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). that not its isopeptidase that binding to this is not related to reported an protein which is to T. H. Suzuki T. A. A. T. T. Tanaka K. M. A. Mol. Cell. Biol. 2002; 22: PubMed Scopus Google Scholar). The domain is in the of from the catalytic was to the of in its catalytic formation and the signal in de-SUMOylation through a in of the have through a (14Cheng J. Kang X. Zhang S. Yeh E.T. Cell. 2007; 131: 584-595Abstract Full Text Full Text PDF PubMed Scopus (499) Google Scholar). at much SENP1–/– not SENP2 provide important SENP1 and SENP2 in cells. are not able to for each in the SENP1–/– and that was only in the SENP1–/– cells. SENP1 and SENP2 have This is important because of the in systems will not be able to the activity these two closely related nucleolar localization of SENP3 that it may regulate of nucleolar function (19Nishida T. Tanaka H. Yasuda H. Eur. J. Biochem. 2000; 267: 6423-6427Crossref PubMed Scopus (143) Google Scholar, 20Gong L. Yeh E.T. J. Biol. Chem. 2006; 281: 15869-15877Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar, 21Di Bacco A. Ouyang J. Lee H.Y. Catic A. Ploegh H. Gill G. Mol. Cell. Biol. 2006; 26: 4489-4498Crossref PubMed Scopus (143) Google Scholar). In SENP3 SUMO2/3 as substrates (20Gong L. Yeh E.T. J. Biol. Chem. 2006; 281: 15869-15877Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar, 21Di Bacco A. Ouyang J. Lee H.Y. Catic A. Ploegh H. Gill G. Mol. Cell. Biol. 2006; 26: 4489-4498Crossref PubMed Scopus (143) Google Scholar). two have the number of SENP3 substrates. SENP3 has to with a in M. T. D. S. PubMed Scopus Google Scholar). SENP3 in and modification of by in of SENP3 by with nucleolar processing and the of the to the a to of SENP3 as an essential for of SENP5 by in nuclear with of cells. that SENP5 may a in Bacco A. Ouyang J. Lee H.Y. Catic A. Ploegh H. Gill G. Mol. Cell. Biol. 2006; 26: 4489-4498Crossref PubMed Scopus (143) Google Scholar). for SENP5 is the A. P. M. J. Cell 2007; PubMed Scopus Google Scholar). of SENP5 SUMO1 from a number of substrates and SENP5 by to of The of SENP5 also in an in SENP5 may a in the of and It is are a for SENP5 because SENP5 is a nucleolar protease and SUMO2/3 as substrates. is a in of SENP6 localization in the The that SENP6 is in the (22Kim K.I. Baek S.H. Jeon Y.J. Nishimori S. Suzuki T. S. N. Saitoh H. Tanaka K. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar), but and have that SENP6 is in the (18Cheng J. Bawa T. Lee P. Gong L. Yeh E.T. Neoplasia (N. Y.). 2006; 8: 667-676Crossref PubMed Scopus (185) Google Scholar, 23Mukhopadhyay D. Ayaydin F. Kolli N. Tan S.H. Anan T. Kametaka A. Azuma Y. Wilkinson K.D. Dasso M. J. Cell Biol. 2006; 174: 939-949Crossref PubMed Scopus (126) Google Scholar). SENP6 of and into (23Mukhopadhyay D. Ayaydin F. Kolli N. Tan S.H. Anan T. Kametaka A. Azuma Y. Wilkinson K.D. Dasso M. J. Cell Biol. 2006; 174: 939-949Crossref PubMed Scopus (126) Google Scholar). It is not SENP6 is involved in the of in Here, I would to to the at the of this can a limited number of SENPs regulate a large of substrates in mammalian contains an N-terminal sequence that is involved in cellular localization. are also nuclear localization signals and nuclear export signals in of the the SENPs not be as proteases that are limited to a single cellular localization. In the SENPs can be regulated by their and export signals through A example is the of and nuclear localization of SENP1 by X. Y. L. Y. D. Zhang H. Y. Kim Y.O. Kim Y. S. Cell PubMed Scopus Google Scholar). to regulate the SENPs is through and regulation. have that SENP1 is by and (18Cheng J. Bawa T. Lee P. Gong L. Yeh E.T. Neoplasia (N. Y.). 2006; 8: 667-676Crossref PubMed Scopus (185) Google Scholar, T. J. Yeh E.T. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). were also reported for of which to de-SUMOylation of N. S. S. Kamitani S. Y. T. T. Biochem. PubMed Scopus Google Scholar). also have that SENP1 is regulated by and has a This can be regulated by and the of each can be regulated by The third is to regulate the binding of SENPs to their substrates. example is that as and the binding of SENP1 to Y. J. N. Zhang X. K. Nat. Cell Biol. 2007; PubMed Scopus Google Scholar). example is a of is by SUMO and is with regulatory Y. I. K. M. T. K. K. N. T. Nat. Med. PubMed Scopus Google Scholar). of is by SENP1 and with The is to regulate the activity of the It has that at in the of SUMO This is to and reversible of enzymes through the formation of the catalytic of the SUMO and the Ubc9 G. Melchior F. Mol. Cell. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). has to formation of an of SENP1 the and a L.S. J. 22: PubMed Scopus Google Scholar). This reversible modification is also in Ulp1 but not in a of these SENPs be able to regulate a large number of biological systems in a In the of will reveal that will of this I H. M. J. T. S. X. T. and L. Gong for to in this