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The In Vivo Functions of Desumoylating Enzymes

Part of the Subcellular Biochemistry book series (SCBI, volume 54)

Abstract

This chapter reviews the current literature to highlight the biological mechanisms mediated via the enzymatic actions of the SUMO-specific protease family. All members of this cysteine protease family express isopeptidase activity to deSUMOylate conjugated cellular protein targets. Here, we discuss how SUMO proteases discriminate amongst the SUMOylated targets based on subcellular localization and conjugated SUMO isoform. Several signal transduction pathways modulate endogenous levels of the deSUMOylating enzymes to regulate cell growth, cell cycle progression and gene transcription. The ability of specific proteases to mediate these cellular events is presented. In addition, we examine cases in which aberrant SUMO protease expression affects normal embryonic development, carcinogenesis and the onset of additional pathophysiological conditions.

Keywords

Cell Cycle Progression Catalytical Domain Cysteine Protease Pathophysiological Condition Regulate Cell Growth 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Li SJ, Hochstrasser M. A new protease required for cell-cycle progression in yeast. Nature 1999; 398:246–51.PubMedCrossRefGoogle Scholar
  2. 2.
    Li SJ, Hochstrasser M. The yeast ULP2 (SMT4) gene encodes a novel protease specific for the ubiquitin-like Smt3 protein. Mol Cell Biol 2000; 20:2367–77.PubMedCrossRefGoogle Scholar
  3. 3.
    Yeh ET, Gong L, Kamitani T. Ubiquitin-like proteins: new wines in new bottles. Gene 2000; 248:1–14.PubMedCrossRefGoogle Scholar
  4. 4.
    Gan-Erdene T, Nagamalleswari K, Yin L et al. Identification and characterization of DE N1, a deneddylase of the ULP family. J Biol Chem 2003; 278:28892–900.PubMedCrossRefGoogle Scholar
  5. 5.
    Cheng J, Bawa T, Lee P et al. Role of desumoylation in the development of prostate cancer. Neoplasia 2006; 8:667–76.PubMedCrossRefGoogle Scholar
  6. 6.
    Yeh ET. SUMOylation and De-SUMOylation: wrestling with life’s processes. J Biol Chem 2009; 284:8223–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Hay RT. SUMO-specific proteases: a twist in the tail. Trends Cell Biol 2007; 17:370–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Bohren KM, Nadkarni V, Song JH et al. A M55V polymorphism in a novel SUMO gene (SUMO-4) differentially activates heat shock transcription factors and is associated with susceptibility to type I diabetes mellitus. J Biol Chem 2004; 279:27233–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Owerbach D, McKay EM, Yeh ET et al. A proline-90 residue unique to SUMO-4 prevents maturation and sumoylation. Biochem Biophys Res Commun 2005; 337:517–20.PubMedCrossRefGoogle Scholar
  10. 10.
    Murtas G, Reeves PH, Fu YF et al. A nuclear protease required for flowering-time regulation in Arabidopsis reduces the abundance of SMALL UBIQUITIN-RELATED MODIFIER conjugates. Plant Cell 2003; 15:2308–19.PubMedCrossRefGoogle Scholar
  11. 11.
    Colby T, Matthai A, Boeckelmann A et al. SUMO-conjugating and SUMO-deconjugating enzymes from Arabidopsis. Plant Physiol 2006; 142:318–32.PubMedCrossRefGoogle Scholar
  12. 12.
    Chosed R, Mukherjee S, Lois LM et al. Evolution of a signalling system that incorporates both redundancy and diversity: Arabidopsis SUMOylation. Biochem J 2006; 398:521–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Reverter D, Lima CD. Structural basis for SENP2 protease interactions with SUMO precursors and conjugated substrates. Nat Struct Mol Biol 2006; 13:1060–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Mikolajczyk J, Drag M, Bekes M et al. Small ubiquitin-related modifier (SUMO)-specific proteases: profiling the specificities and activities of human SENPs. J Biol Chem 2007; 282:26217–24.PubMedCrossRefGoogle Scholar
  15. 15.
    Shen L, Tatham MH, Dong C et al. SUMO protease SENP1 induces isomerization of the scissile peptide bond. Nat Struct Mol Biol 2006; 13:1069–77.PubMedCrossRefGoogle Scholar
  16. 16.
    Cheng J, Kang X, Zhang S et al. SUMO-specific protease 1 is essential for stabilization of HIF1alpha during hypoxia. Cell 2007; 131:584–95.PubMedCrossRefGoogle Scholar
  17. 17.
    Di Bacco A, Ouyang J, Lee HY et al. The SUMO-specific protease SENP5 is required for cell division. Mol Cell Biol 2006; 26:4489–98.PubMedCrossRefGoogle Scholar
  18. 18.
    Lima CD, Reverter D. Structure of the human SENP7 catalytic domain and poly-SUMO deconjugation activities for SENP6 and SENP7. J Biol Chem 2008; 283:32045–55.PubMedCrossRefGoogle Scholar
  19. 19.
    Li SJ, Hochstrasser M. The Ulp1 SUMO isopeptidase: distinct domains required for viability, nuclear envelope localization and substrate specificity. J Cell Biol 2003; 160:1069–81.PubMedCrossRefGoogle Scholar
  20. 20.
    Zhang H, Saitoh H, Matunis MJ. Enzymes of the SUMO modification pathway localize to filaments of the nuclear pore complex. Mol Cell Biol 2002; 22:6498–508.PubMedCrossRefGoogle Scholar
  21. 21.
    Hang J, Dasso M. Association of the human SUMO-1 protease SENP2 with the nuclear pore. J Biol Chem 2002; 277:19961–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Kim YH, Sung KS, Lee SJ et al. Desumoylation of homeodomain-interacting protein kinase 2 (HIPK2) through the cytoplasmic-nuclear shuttling of the SUMO-specific protease SENP1. FEBS Lett 2005; 579:6272–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Itahana Y, Yeh ET, Zhang Y. Nucleocytoplasmic shuttling modulates activity and ubiquitination-dependent turnover of SUMO-specific protease 2. Mol Cell Biol 2006; 26:4675–89.PubMedCrossRefGoogle Scholar
  24. 24.
    Nishida T, Tanaka H, Yasuda H. A novel mammalian Smt3-specific isopeptidase 1 (SMT3IP1) localized in the nucleolus at interphase. Eur J Biochem 2000; 267:6423–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Yun C, Wang Y, Mukhopadhyay D et al. Nucleolar protein B23/nucleophosmin regulates the vertebrate SUMO pathway through SENP3 and SENP5 proteases. J Cell Biol 2008; 183:589–95.PubMedCrossRefGoogle Scholar
  26. 26.
    Gong L, Yeh ET. Characterization of a family of nucleolar SUMO-specific proteases with preference for SUMO-2 or SUMO-3. J Biol Chem 2006; 281:15869–77.PubMedCrossRefGoogle Scholar
  27. 27.
    Haindl M, Harasim T, Eick D et al. The nucleolar SUMO-specific protease SENP3 reverses SUMO modification of nucleophosmin and is required for rRNA processing. EMBO Rep 2008; 9:273–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Kim KI, Baek SH, Jeon YJ et al. A new SUMO-1-specific protease, SUSP1, that is highly expressed in reproductive organs. J Biol Chem 2000; 275:14102–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Choi SJ, Chung SS, Rho EJ et al. Negative modulation of RXRalpha transcriptional activity by small ubiquitin-related modifier (SUMO) modification and its reversal by SUMO-specific protease SUSP1. J Biol Chem 2006; 281:30669–77.PubMedCrossRefGoogle Scholar
  30. 30.
    Mukhopadhyay D, Ayaydin F, Kolli N et al. SUSP1 antagonizes formation of highly SUMO2/3-conjugated species. J Cell Biol 2006; 174:939–49.PubMedCrossRefGoogle Scholar
  31. 31.
    Shen LN, Geoffroy MC, Jaffray EG et al. Characterization of SENP7, a SUMO-2/3-specific isopeptidase. Biochem J 2009; 421:223–30.PubMedCrossRefGoogle Scholar
  32. 32.
    Bawa-Khalfe T, Cheng J, Wang Z et al. Induction of the SUMO-specific protease 1 transcription by the androgen receptor in prostate cancer cells. J Biol Chem 2007; 282:37341–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Ohbayashi N, Kawakami S, Muromoto R et al. The IL-6 family of cytokines modulates STAT3 activation by desumoylation of PML through SENP1 induction. Biochem Biophys Res Commun 2008; 371:823–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Kuo ML, den Besten W, Thomas MC et al. Arf-induced turnover of the nucleolar nucleophosmin-associated SUMO-2/3 protease Senp3. Cell Cycle 2008; 7:3378–87.PubMedCrossRefGoogle Scholar
  35. 35.
    Huang C, Han Y, Wang Y et al. SENP3 is responsible for HIF-1 transactivation under mild oxidative stress via p300 de-SUMOylation. EMBO J 2009.Google Scholar
  36. 36.
    Ross S, Best JL, Zon LI et al. SUMO-1 modification represses Sp3 transcriptional activation and modulates its subnuclear localization. Mol Cell 2002; 10:831–42.PubMedCrossRefGoogle Scholar
  37. 37.
    Gregoire S, Yang XJ. Association with class IIa histone deacetylases upregulates the sumoylation of MEF2 transcription factors. Mol Cell Biol 2005; 25:2273–87.PubMedCrossRefGoogle Scholar
  38. 38.
    Cheng J, Wang D, Wang Z et al. SENP1 enhances androgen receptor-dependent transcription through desumoylation of histone deacetylase 1. Mol Cell Biol 2004; 24:6021–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Kaikkonen S, Jaaskelainen T, Karvonen U et al. SUMO-specific protease 1 (SENP1) reverses the hormone-augmented SUMOylation of androgen receptor and modulates gene responses in prostate cancer cells. Mol Endocrinol 2009; 23:292–307.PubMedCrossRefGoogle Scholar
  40. 40.
    Cheng J, Perkins ND, Yeh ET. Differential regulation of c-Jun-dependent transcription by SUMO-specific proteases. J Biol Chem 2005; 280:14492–8.PubMedCrossRefGoogle Scholar
  41. 41.
    Best JL, Ganiatsas S, Agarwal S et al. SUMO-1 protease-1 regulates gene transcription through PML. Mol Cell 2002; 10:843–55.PubMedCrossRefGoogle Scholar
  42. 42.
    Kadoya T, Yamamoto H, Suzuki T et al. Desumoylation activity of Axam, a novel Axin-binding protein, is involved in downregulation of beta-catenin. Mol Cell Biol 2002; 22:3803–19.PubMedCrossRefGoogle Scholar
  43. 43.
    Yamamoto H, Ihara M, Matsuura Y et al. Sumoylation is involved in beta-catenin-dependent activation of Tcf-4. EMBO J 2003; 22:2047–59.PubMedCrossRefGoogle Scholar
  44. 44.
    Shitashige M, Satow R, Honda K et al. Regulation of Wnt signaling by the nuclear pore complex. Gastroenterology 2008; 134:1961–1971, 1971 e1961–1964.PubMedCrossRefGoogle Scholar
  45. 45.
    Nishida T, Kaneko F, Kitagawa M et al. Characterization of a novel mammalian SUMO-1/Smt3-specific isopeptidase, a homologue of rat axam, which is an axin-binding protein promoting beta-catenin degradation. J Biol Chem 2001; 276:39060–6.PubMedCrossRefGoogle Scholar
  46. 46.
    Vethantham V, Rao N, Manley JL. Sumoylation modulates the assembly and activity of the pre-mRNA 3’ processing complex. Mol Cell Biol 2007; 27:8848–58.PubMedCrossRefGoogle Scholar
  47. 47.
    Taylor DL, Ho JC, Oliver A et al. Cell-cycle-dependent localisation of Ulp1, a Schizosaccharomyces pombe Pmt3 (SUMO)-specific protease. J Cell Sci 2002; 115:1113–22.PubMedGoogle Scholar
  48. 48.
    Schwartz DC, Felberbaum R, Hochstrasser M. The Ulp2 SUMO protease is required for cell division following termination of the DNA damage checkpoint. Mol Cell Biol 2007; 27:6948–61.PubMedCrossRefGoogle Scholar
  49. 49.
    Yates KE, Korbel GA, Shtutman M et al. Repression of the SUMO-specific protease Senp1 induces p53-dependent premature senescence in normal human fibroblasts. Aging Cell 2008; 7:609–21.PubMedCrossRefGoogle Scholar
  50. 50.
    Chiu SY, Asai N, Costantini F et al. SUMO-specific protease 2 is essential for modulating p53-Mdm2 in development of trophoblast stem cell niches and lineages. PLoS Biol 2008; 6:e310.PubMedCrossRefGoogle Scholar
  51. 51.
    Li X, Zhang R, Luo D et al. Tumor necrosis factor alpha-induced desumoylation and cytoplasmic translocation of homeodomain-interacting protein kinase 1 are critical for apoptosis signal-regulating kinase 1-JNK/ p38 activation. J Biol Chem 2005; 280:15061–70.PubMedCrossRefGoogle Scholar
  52. 52.
    Li X, Luo Y, Yu L et al. SENP1 mediates TNF-induced desumoylation and cytoplasmic translocation of HIPK1 to enhance ASK1-dependent apoptosis. Cell Death Differ 2008; 15:739–50.PubMedCrossRefGoogle Scholar
  53. 53.
    Yamaguchi T, Sharma P, Athanasiou M et al. Mutation of SENP1/SuPr-2 reveals an essential role for desumoylation in mouse development. Mol Cell Biol 2005; 25:5171–82.PubMedCrossRefGoogle Scholar
  54. 54.
    McDoniels-Silvers AL, Nimri CF et al. Differential gene expression in human lung adenocarcinomas and squamous cell carcinomas. Clin Cancer Res 2002; 8:1127–38.PubMedGoogle Scholar
  55. 55.
    Veltman IM, Vreede LA, Cheng J et al. Fusion of the SUMO/Sentrin-specific protease 1 gene SENP1 and the embryonic polarity-related mesoderm development gene MESDC2 in a patient with an infantile teratoma and a constitutional t(12; 15)(q13; q25). Hum Mol Genet 2005; 14:1955–63.PubMedCrossRefGoogle Scholar
  56. 56.
    Tagawa H, Miura I, Suzuki R et al. Molecular cytogenetic analysis of the breakpoint region at 6q21-22 in T-cell lymphoma/leukemia cell lines. Genes Chromosomes Cancer 2002; 34:175–85.PubMedCrossRefGoogle Scholar
  57. 57.
    Moschos SJ, Smith AP, Mandic M et al. SAGE and antibody array analysis of melanoma-infiltrated lymph nodes: identification of Ubc9 as an important molecule in advanced-stage melanomas. Oncogene 2007; 26:4216–25.PubMedCrossRefGoogle Scholar
  58. 58.
    Mo YY, Yu Y, Theodosiou E et al. A role for Ubc9 in tumorigenesis. Oncogene 2005; 24:2677–83.PubMedCrossRefGoogle Scholar
  59. 59.
    Jacques C, Baris O, Prunier-Mirebeau D et al. Two-step differential expression analysis reveals a new set of genes involved in thyroid oncocytic tumors. J Clin Endocrinol Metab 2005; 90:2314–20.PubMedCrossRefGoogle Scholar
  60. 60.
    Dunnebier T, Bermejo JL, Haas S et al. Common variants in the UBC9 gene encoding the SUMO-conjugating enzyme are associated with breast tumor grade. Int J Cancer 2009; 125:596–602.PubMedCrossRefGoogle Scholar
  61. 61.
    Wang L, Banerjee S. Differential PIAS3 expression in human malignancy. Oncol Rep 2004; 11:1319–24.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2010

Authors and Affiliations

  1. 1.Department of CardiologyAnderson Cancer CenterHoustonUSA

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