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Concepts in sumoylation: a decade on

Key Points

  • SUMO (small ubiquitin-related modifier) proteins are 10-kD polypeptides that function as reversible post-translational protein modifiers. They form isopeptide bonds with ɛ-amino groups of acceptor Lys residues in hundreds of target proteins in a process termed sumoylation.

  • Sumoylation requires a cascade of enzymatic steps that involves an E1 activating enzyme, an E2 conjugating enzyme and, in most cases, an E3 SUMO ligase. Owing to SUMO-specific isopeptidases, this modification is highly dynamic.

  • Acceptor Lys residues in target proteins are frequently found in the consensus motif ΨKxE (in which Ψ is a branched aliphatic amino acid and x is any amino acid), although the number of targets with non-consensus acceptor sites is steadily increasing.

  • Sumoylation alters the molecular interactions of modified target proteins by masking or adding interaction surfaces. Downstream consequences, which are target dependent, include changes in localization, activity and protein stability.

  • A short non-covalent SUMO-interaction/binding motif (SIM/SBM) has been identified in selected SUMO enzymes, targets and downstream effectors. This motif contributes to the mechanism and consequences of sumoylation.

  • Reversible sumoylation contributes to many distinct pathways, such as chromatin structure, DNA repair, transcription, cell-cycle progression and trafficking. Targets can be found in the nucleus, the cytoplasm, the plasma membrane and organelles such as the endoplasmic reticulum and mitochondria.

Abstract

A decade has passed since SUMO (small ubiquitin-related modifier) was discovered to be a reversible post-translational protein modifier. During this time many enzymes that participate in regulated SUMO-conjugation and -deconjugation pathways have been identified and characterized. In parallel, the search for SUMO substrates has produced a long list of targets, which appear to be involved in most cellular functions. Sumoylation is a highly dynamic process and its outcomes are extremely diverse, ranging from changes in localization to altered activity and, in some cases, stability of the modified protein. At first glance, these effects have nothing in common; however, it seems that they all result from changes in the molecular interactions of the sumoylated proteins.

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Figure 1: The mechanism of reversible sumoylation.
Figure 2: Molecular consequences of sumoylation.
Figure 3: Low-level transcription factor sumoylation can result in quantitative repression.
Figure 4: Thymine DNA glycosylase requires sumoylation and desumoylation for each catalytic cycle.
Figure 5: Sumoylated proteins are found throughout the cell.

References

  1. Meluh, P. B. & Koshland, D. Evidence that the MIF2 gene of Saccharomyces cerevisiae encodes a centromere protein with homology to the mammalian centromere protein CENP-C. Mol. Biol. Cell 6, 793–807 (1995).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. Shen, Z., Pardington-Purtymun, P. E., Comeaux, J. C., Moyzis, R. K. & Chen, D. J. UBL1, a human ubiquitin-like protein associating with human RAD51/RAD52 proteins. Genomics 36, 271–279 (1996).

    CAS  PubMed  Article  Google Scholar 

  3. Okura, T. et al. Protection against Fas/APO-1- and tumor necrosis factor-mediated cell death by a novel protein, sentrin. J. Immunol. 157, 4277–4281 (1996).

    CAS  PubMed  Google Scholar 

  4. Boddy, M. N., Howe, K., Etkin, L. D., Solomon, E. & Freemont, P. S. PIC1, a novel ubiquitin-like protein which interacts with the PML component of a multiprotein complex that is disrupted in acute promyelocytic leukaemia. Oncogene 13, 971–982 (1996).

    CAS  PubMed  Google Scholar 

  5. Matunis, M. J., Coutavas, E. & Blobel, G. A novel ubiquitin-like modification modulates the partitioning of the Ran-GTPase-activating protein RanGAP1 between the cytosol and the nuclear pore complex. J. Cell Biol. 135, 1457–1470 (1996). Identifies SUMO1 as a reversible modifier, together with reference 6, and demonstrates that sumoylation can lead to altered localization.

    CAS  PubMed  Article  Google Scholar 

  6. Mahajan, R., Delphin, C., Guan, T., Gerace, L. & Melchior, F. A small ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex protein RanBP2. Cell 88, 97–107 (1997). Identifies SUMO1 as a reversible modifier, together with reference 5, and demonstrates that sumoylation can lead to novel protein interactions.

    CAS  PubMed  Article  Google Scholar 

  7. Gill, G. Something about SUMO inhibits transcription. Curr. Opin. Genet. Dev. 15, 536–541 (2005).

    CAS  PubMed  Article  Google Scholar 

  8. Scheschonka, A., Tang, Z. & Betz, H. Sumoylation in neurons: nuclear and synaptic roles? Trends Neurosci. 30, 85–91 (2007).

    CAS  PubMed  Article  Google Scholar 

  9. Johnson, E. S. Protein modification by SUMO. Annu. Rev. Biochem. 73, 355–382 (2004).

    CAS  PubMed  Article  Google Scholar 

  10. Melchior, F., Schergaut, M. & Pichler, A. SUMO: ligases, isopeptidases and nuclear pores. Trends Biochem. Sci. 28, 612–618 (2003).

    CAS  PubMed  Article  Google Scholar 

  11. Boggio, R. & Chiocca, S. Viruses and sumoylation: recent highlights. Curr. Opin. Microbiol. 9, 430–436 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  12. Girdwood, D. W., Tatham, M. H. & Hay, R. T. SUMO and transcriptional regulation. Semin. Cell Dev. Biol. 15, 201–210 (2004).

    CAS  PubMed  Article  Google Scholar 

  13. Seeler, J. S. & Dejean, A. Nuclear and unclear functions of SUMO. Nature Rev. Mol. Cell Biol. 4, 690–699 (2003).

    CAS  Article  Google Scholar 

  14. Bayer, P. et al. Structure determination of the small ubiquitin-related modifier SUMO-1. J. Mol. Biol. 280, 275–286 (1998).

    CAS  PubMed  Article  Google Scholar 

  15. Mossessova, E. & Lima, C. D. Ulp1–SUMO crystal structure and genetic analysis reveal conserved interactions and a regulatory element essential for cell growth in yeast. Mol. Cell 5, 865–876 (2000).

    CAS  PubMed  Article  Google Scholar 

  16. Bernier-Villamor, V., Sampson, D. A., Matunis, M. J. & Lima, C. D. Structural basis for E2-mediated SUMO conjugation revealed by a complex between ubiquitin-conjugating enzyme Ubc9 and RanGAP1. Cell 108, 345–356 (2002). The crystal structure reported in this paper demonstrates how the single E2 conjugating enzyme UBC9 recognizes conventional SUMO-acceptor sites in its targets.

    CAS  PubMed  Article  Google Scholar 

  17. Guo, D. et al. A functional variant of SUMO4, a new IκBα modifier, is associated with type 1 diabetes. Nature Genet. 36, 837–841 (2004).

    CAS  PubMed  Article  Google Scholar 

  18. Melchior, F. SUMO — nonclassical ubiquitin. Annu. Rev. Cell Dev. Biol. 16, 591–626 (2000).

    CAS  PubMed  Article  Google Scholar 

  19. Saitoh, H. & Hinchey, J. Functional heterogeneity of small ubiquitin-related protein modifiers SUMO-1 versus SUMO-2/3. J. Biol. Chem. 275, 6252–6258 (2000).

    CAS  PubMed  Article  Google Scholar 

  20. Rosas-Acosta, G., Russell, W. K., Deyrieux, A., Russell, D. H. & Wilson, V. G. A universal strategy for proteomic studies of SUMO and other ubiquitin-like modifiers. Mol. Cell Proteomics 4, 56–72 (2005).

    CAS  PubMed  Article  Google Scholar 

  21. Vertegaal, A. C. et al. Distinct and overlapping sets of SUMO-1 and SUMO-2 target proteins revealed by quantitative proteomics. Mol. Cell Proteomics 5, 2298–2310 (2006).

    CAS  PubMed  Article  Google Scholar 

  22. Owerbach, D., McKay, E. M., Yeh, E. T., Gabbay, K. H. & Bohren, K. M. A proline-90 residue unique to SUMO-4 prevents maturation and sumoylation. Biochem. Biophys. Res. Commun. 337, 517–520 (2005).

    CAS  PubMed  Article  Google Scholar 

  23. Johnson, E. S., Schwienhorst, I., Dohmen, R. J. & Blobel, G. The ubiquitin-like protein Smt3p is activated for conjugation to other proteins by an Aos1p/Uba2p heterodimer. EMBO J. 16, 5509–5519 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Fraser, A. G. et al. Functional genomic analysis of C. elegans chromosome I by systematic RNA interference. Nature 408, 325–330 (2000).

    CAS  PubMed  Article  Google Scholar 

  25. Saracco, S. A., Miller, M. J., Kurepa, J. & Vierstra, R. D. Genetic analysis of sumoylation in Arabidopsis: heat-induced conjugation of SUMO1 and 2 is essential. Plant Physiol. 145, 119–134 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. Nacerddine, K. et al. The SUMO pathway is essential for nuclear integrity and chromosome segregation in mice. Dev. Cell 9, 769–779 (2005).

    CAS  PubMed  Article  Google Scholar 

  27. Tanaka, K. et al. Characterization of a fission yeast SUMO-1 homologue, Pmt3p, required for multiple nuclear events, including the control of telomere length and chromosome segregation. Mol. Cell. Biol. 19, 8660–8672 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. Alkuraya, F. S. et al. SUMO1 haploinsufficiency leads to cleft lip and palate. Science 313, 1751 (2006). Finds reduced SUMO1 expression in a patient with cleft lip and shows that mice with one defective SUMO1 allele develop a similar phenotype. Moreover, it shows that SUMO1 is essential in mice.

    PubMed  Article  Google Scholar 

  29. Desterro, J. M., Rodriguez, M. S., Kemp, G. D. & Hay, R. T. Identification of the enzyme required for activation of the small ubiquitin-like protein SUMO-1. J. Biol. Chem. 274, 10618–10624 (1999).

    CAS  PubMed  Article  Google Scholar 

  30. Okuma, T., Honda, R., Ichikawa, G., Tsumagari, N. & Yasuda, H. In vitro SUMO-1 modification requires two enzymatic steps, E1 and E2. Biochem. Biophys. Res. Commun. 254, 693–698 (1999).

    CAS  PubMed  Article  Google Scholar 

  31. Gong, L., Li, B., Millas, S. & Yeh, E. T. Molecular cloning and characterization of human AOS1 and UBA2, components of the sentrin-activating enzyme complex. FEBS Lett. 448, 185–189 (1999).

    CAS  PubMed  Article  Google Scholar 

  32. Johnson, E. S. & Blobel, G. Ubc9p is the conjugating enzyme for the ubiquitin-like protein Smt3p. J. Biol. Chem. 272, 26799–26802 (1997).

    CAS  PubMed  Article  Google Scholar 

  33. Desterro, J. M., Thomson, J. & Hay, R. T. Ubch9 conjugates SUMO but not ubiquitin. FEBS Lett. 417, 297–300 (1997).

    CAS  PubMed  Article  Google Scholar 

  34. Lee, G. W. et al. Modification of Ran GTPase-activating protein by the small ubiquitin-related modifier SUMO-1 requires Ubc9, an E2-type ubiquitin-conjugating enzyme homologue. J. Biol. Chem. 273, 6503–6507 (1998).

    CAS  PubMed  Article  Google Scholar 

  35. Saitoh, H. et al. Ubc9p and the conjugation of SUMO-1 to RanGAP1 and RanBP2. Curr. Biol. 8, 121–124 (1998).

    CAS  PubMed  Article  Google Scholar 

  36. Hochstrasser, M. SP-RING for SUMO: new functions bloom for a ubiquitin-like protein. Cell 107, 5–8 (2001).

    CAS  PubMed  Article  Google Scholar 

  37. Sharrocks, A. D. PIAS proteins and transcriptional regulation — more than just SUMO E3 ligases? Genes Dev. 20, 754–758 (2006).

    CAS  PubMed  Article  Google Scholar 

  38. Johnson, E. S. & Gupta, A. A. An E3-like factor that promotes SUMO conjugation to the yeast septins. Cell 106, 735–744 (2001). Together with reference 39 describes the first SUMO E3 ligases, Siz1 and Siz2. Identification of their mammalian homologues, the PIAS proteins, as E3 ligases followed shortly thereafter (see references 40 and 45).

    CAS  PubMed  Article  Google Scholar 

  39. Takahashi, Y., Kahyo, T., Toh, E. A., Yasuda, H. & Kikuchi, Y. Yeast Ull1/Siz1 is a novel SUMO1/Smt3 ligase for septin components and functions as an adaptor between conjugating enzyme and substrates. J. Biol. Chem. 276, 48973–48977 (2001).

    CAS  PubMed  Article  Google Scholar 

  40. Kahyo, T., Nishida, T. & Yasuda, H. Involvement of PIAS1 in the sumoylation of tumor suppressor p53. Mol. Cell 8, 713–718 (2001).

    CAS  PubMed  Article  Google Scholar 

  41. Schmidt, D. & Muller, S. Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity. Proc. Natl Acad. Sci. USA 99, 2872–2877 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. Nishida, T. & Yasuda, H. PIAS1 and PIASxα function as SUMO-E3 ligases toward androgen receptor and repress androgen receptor-dependent transcription. J. Biol. Chem. 277, 41311–41317 (2002).

    CAS  PubMed  Article  Google Scholar 

  43. Sapetschnig, A. et al. Transcription factor Sp3 is silenced through SUMO modification by PIAS1. EMBO J. 21, 5206–5215 (2002). Provides a clear example for the role of SUMO in inhibiting transcription: PIAS1-dependent sumoylation in the inhibitory domain silences Sp3 without impairing DNA binding.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Nakagawa, K. & Yokosawa, H. PIAS3 induces SUMO-1 modification and transcriptional repression of IRF-1. FEBS Lett. 530, 204–208 (2002).

    CAS  PubMed  Article  Google Scholar 

  45. Sachdev, S. et al. PIASy, a nuclear matrix-associated SUMO E3 ligase, represses LEF1 activity by sequestration into nuclear bodies. Genes Dev. 15, 3088–3103 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Kotaja, N., Karvonen, U., Janne, O. A. & Palvimo, J. J. PIAS proteins modulate transcription factors by functioning as SUMO-1 ligases. Mol. Cell. Biol. 22, 5222–5234 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. Zhao, X. & Blobel, G. A SUMO ligase is part of a nuclear multiprotein complex that affects DNA repair and chromosomal organization. Proc. Natl Acad. Sci. USA 102, 4777–4782 (2005). Together with references 48 and 49 identifies Mms21/Nse2, a component of the Smc5–Smc6 complex, as a novel SP-RING-type SUMO E3 ligase.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. Andrews, E. A. et al. Nse2, a component of the Smc5–6 complex, is a SUMO ligase required for the response to DNA damage. Mol. Cell. Biol. 25, 185–196 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. Potts, P. R. & Yu, H. Human MMS21/NSE2 is a SUMO ligase required for DNA repair. Mol. Cell. Biol. 25, 7021–7032 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. Potts, P. R. & Yu, H. The SMC5/6 complex maintains telomere length in ALT cancer cells through SUMOylation of telomere-binding proteins. Nature Struct. Mol. Biol. 14, 581–590 (2007). Links sumoylation to telomerase-independent telomere maintenance in certain cancer cells.

    CAS  Article  Google Scholar 

  51. Cheng, C. H. et al. SUMO modifications control assembly of synaptonemal complex and polycomplex in meiosis of Saccharomyces cerevisiae. Genes Dev. 20, 2067–2081 (2006). In addition to the description of Zip3 as a meiosis-specific SUMO E3 ligase, this paper suggests a role for SUMO-chain formation in synaptonemal-complex formation and sporulation.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. Pichler, A., Gast, A., Seeler, J. S., Dejean, A. & Melchior, F. The nucleoporin RanBP2 has SUMO1 E3 ligase activity. Cell 108, 109–120 (2002). Identification of the nucleoporin RanBP2 as a unique E3 ligase, the catalytic domain of which is unrelated in sequence to HECT or RING E3 ligases (see also reference 53).

    CAS  PubMed  Article  Google Scholar 

  53. Pichler, A., Knipscheer, P., Saitoh, H., Sixma, T. K. & Melchior, F. The RanBP2 SUMO E3 ligase is neither HECT- nor RING-type. Nature Struct. Mol. Biol. 11, 984–991 (2004).

    CAS  Article  Google Scholar 

  54. Reverter, D. & Lima, C. D. Insights into E3 ligase activity revealed by a SUMO–RanGAP1–Ubc9–Nup358 complex. Nature 435, 687–692 (2005). A crystal structure suggests that RanBP2 functions as an E3 ligase by binding both SUMO and UBC9 to position the SUMO–E2 thioester bond in an optimal orientation to enhance conjugation.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. Tatham, M. H. et al. Unique binding interactions among Ubc9, SUMO and RanBP2 reveal a mechanism for SUMO paralog selection. Nature Struct. Mol. Biol. 12, 67–74 (2005).

    CAS  Article  Google Scholar 

  56. Kirsh, O. et al. The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase. EMBO J. 21, 2682–2691 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. Kagey, M. H., Melhuish, T. A. & Wotton, D. The polycomb protein Pc2 is a SUMO E3. Cell 113, 127–137 (2003).

    CAS  PubMed  Article  Google Scholar 

  58. Kagey, M. H., Melhuish, T. A., Powers, S. E. & Wotton, D. Multiple activities contribute to Pc2 E3 function. EMBO J. 24, 108–119 (2005).

    CAS  PubMed  Article  Google Scholar 

  59. Zhao, X., Sternsdorf, T., Bolger, T. A., Evans, R. M. & Yao, T. P. Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications. Mol. Cell. Biol. 25, 8456–8464 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. Gregoire, S. & Yang, X. J. Association with class IIa histone deacetylases upregulates the sumoylation of MEF2 transcription factors. Mol. Cell. Biol. 25, 2273–2287 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. Ghisletti, S. et al. Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPARγ. Mol. Cell 25, 57–70 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. Stankovic-Valentin, N. et al. An acetylation/deacetylation-SUMOylation switch through a phylogenetically conserved ψKXEP motif in the tumor suppressor HIC1 regulates transcriptional repression activity. Mol. Cell. Biol. 27, 2661–2675 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. Tatham, M. H. et al. Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9. J. Biol. Chem. 276, 35368–35374 (2001).

    CAS  PubMed  Article  Google Scholar 

  64. Bylebyl, G. R., Belichenko, I. & Johnson, E. S. The SUMO isopeptidase Ulp2 prevents accumulation of SUMO chains in yeast. J. Biol. Chem. 278, 44113–44120 (2003).

    CAS  PubMed  Article  Google Scholar 

  65. Mukhopadhyay, D. et al. SUSP1 antagonizes formation of highly SUMO2/3-conjugated species. J. Cell Biol. 174, 939–949 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. Li, S. J. & Hochstrasser, M. The yeast ULP2 (SMT4) gene encodes a novel protease specific for the ubiquitin-like Smt3 protein. Mol. Cell. Biol. 20, 2367–2377 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. Li, S. J. & Hochstrasser, M. A new protease required for cell-cycle progression in yeast. Nature 398, 246–251 (1999). A biochemical screen of an expression library allowed identification of the first SUMO-specific isopeptidase — Ulp1.

    CAS  PubMed  Article  Google Scholar 

  68. Di Bacco, A. et al. The SUMO-specific protease SENP5 is required for cell division. Mol. Cell. Biol. 26, 4489–4498 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. Gong, L. & Yeh, E. T. Characterization of a family of nucleolar SUMO-specific proteases with preference for SUMO-2 or SUMO-3. J. Biol. Chem. 281, 15869–15877 (2006).

    CAS  PubMed  Article  Google Scholar 

  70. Li, S. J. & Hochstrasser, M. The Ulp1 SUMO isopeptidase: distinct domains required for viability, nuclear envelope localization, and substrate specificity. J. Cell Biol. 160, 1069–1081 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. Hang, J. & Dasso, M. Association of the human SUMO-1 protease SENP2 with the nuclear pore. J. Biol. Chem. 277, 19961–19966 (2002).

    CAS  PubMed  Article  Google Scholar 

  72. Zhang, H., Saitoh, H. & Matunis, M. J. Enzymes of the SUMO modification pathway localize to filaments of the nuclear pore complex. Mol. Cell. Biol. 22, 6498–6508 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. Nishida, T., Tanaka, H. & Yasuda, H. A novel mammalian Smt3-specific isopeptidase 1 (SMT3IP1) localized in the nucleolus at interphase. Eur. J. Biochem. 267, 6423–6427 (2000).

    CAS  PubMed  Article  Google Scholar 

  74. Zunino, R., Schauss, A., Rippstein, P., Andrade-Navarro, M. & McBride, H. M. The SUMO protease SENP5 is required to maintain mitochondrial morphology and function. J. Cell Sci. 120, 1178–1188 (2007).

    CAS  PubMed  Article  Google Scholar 

  75. Gong, L., Millas, S., Maul, G. G. & Yeh, E. T. Differential regulation of sentrinized proteins by a novel sentrin-specific protease. J. Biol. Chem. 275, 3355–3359 (2000).

    CAS  PubMed  Article  Google Scholar 

  76. Bailey, D. & O'Hare, P. Characterization of the localization and proteolytic activity of the SUMO-specific protease, SENP1. J. Biol. Chem. 279, 692–703 (2004).

    CAS  PubMed  Article  Google Scholar 

  77. Kim, K. I. et al. A new SUMO-1-specific protease, SUSP1, that is highly expressed in reproductive organs. J. Biol. Chem. 275, 14102–14106 (2000).

    CAS  PubMed  Article  Google Scholar 

  78. Mukhopadhyay, D. & Dasso, M. Modification in reverse: the SUMO proteases. Trends Biochem. Sci. 32, 286–295 (2007).

    CAS  PubMed  Article  Google Scholar 

  79. Mahajan, R., Gerace, L. & Melchior, F. Molecular characterization of the SUMO-1 modification of RanGAP1 and its role in nuclear envelope association. J. Cell Biol. 140, 259–270 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. Matunis, M. J., Wu, J. & Blobel, G. SUMO-1 modification and its role in targeting the Ran GTPase-activating protein, RanGAP1, to the nuclear pore complex. J. Cell Biol. 140, 499–509 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. Kamitani, T. et al. Identification of three major sentrinization sites in PML. J. Biol. Chem. 273, 26675–26682 (1998).

    CAS  PubMed  Article  Google Scholar 

  82. Sternsdorf, T., Jensen, K., Reich, B. & Will, H. The nuclear dot protein Sp100, characterization of domains necessary for dimerization, subcellular localization, and modification by small ubiquitin-like modifiers. J. Biol. Chem. 274, 12555–12566 (1999).

    CAS  PubMed  Article  Google Scholar 

  83. Desterro, J. M., Rodriguez, M. S. & Hay, R. T. SUMO-1 modification of IκBα inhibits NF-κB activation. Mol. Cell 2, 233–239 (1998). Provided the first example of a protein that can be sumoylated and ubiquitylated at the same Lys residue.

    CAS  PubMed  Article  Google Scholar 

  84. Muller, S. et al. c-Jun and p53 activity is modulated by SUMO-1 modification. J. Biol. Chem. 275, 13321–13329 (2000).

    CAS  PubMed  Article  Google Scholar 

  85. Macauley, M. S. et al. Beads-on-a-string, characterization of ETS-1 sumoylated within its flexible N-terminal sequence. J. Biol. Chem. 281, 4164–4172 (2006).

    CAS  PubMed  Article  Google Scholar 

  86. Pichler, A. et al. SUMO modification of the ubiquitin-conjugating enzyme E2–25K. Nature Struct. Mol. Biol. 12, 264–269 (2005).

    CAS  Article  Google Scholar 

  87. Hietakangas, V. et al. PDSM, a motif for phosphorylation-dependent SUMO modification. Proc. Natl Acad. Sci. USA 103, 45–50 (2006). Phosphorylation adjacent to the conventional SUMO-acceptor site enhances modification of several target proteins.

    CAS  PubMed  Article  Google Scholar 

  88. Hietakangas, V. et al. Phosphorylation of serine 303 is a prerequisite for the stress-inducible SUMO modification of heat shock factor 1. Mol. Cell. Biol. 23, 2953–2968 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. Yang, S. H., Galanis, A., Witty, J. & Sharrocks, A. D. An extended consensus motif enhances the specificity of substrate modification by SUMO. EMBO J. 25, 5083–5093 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. Hoege, C., Pfander, B., Moldovan, G. L., Pyrowolakis, G. & Jentsch, S. RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature 419, 135–141 (2002). Demonstrates that monoubiquitylation, polyubiquitylation and sumoylation of the same Lys residue in a non-consensus SUMO-acceptor site of PCNA serve distinct functions in DNA repair and replication (see also references 92 and 93).

    CAS  Article  PubMed  Google Scholar 

  91. Girdwood, D. et al. p300 transcriptional repression is mediated by SUMO modification. Mol. Cell 11, 1043–1054 (2003).

    CAS  PubMed  Article  Google Scholar 

  92. Papouli, E. et al. Crosstalk between SUMO and ubiquitin on PCNA is mediated by recruitment of the helicase Srs2p. Mol. Cell 19, 123–133 (2005).

    CAS  PubMed  Article  Google Scholar 

  93. Pfander, B., Moldovan, G. L., Sacher, M., Hoege, C. & Jentsch, S. SUMO-modified PCNA recruits Srs2 to prevent recombination during S phase. Nature 436, 428–433 (2005).

    CAS  PubMed  Article  Google Scholar 

  94. Zheng, G. & Yang, Y. C. ZNF76, a novel transcriptional repressor targeting TATA-binding protein, is modulated by sumoylation. J. Biol. Chem. 279, 42410–42421 (2004).

    CAS  PubMed  Article  Google Scholar 

  95. Lin, X. et al. Opposed regulation of corepressor CtBP by SUMOylation and PDZ binding. Mol. Cell 11, 1389–1396 (2003).

    CAS  PubMed  Article  Google Scholar 

  96. Macauley, M. S. et al. Structural and dynamic independence of isopeptide-linked RanGAP1 and SUMO-1. J. Biol. Chem. 279, 49131–49137 (2004).

    CAS  PubMed  Article  Google Scholar 

  97. Hardeland, U., Steinacher, R., Jiricny, J. & Schar, P. Modification of the human thymine-DNA glycosylase by ubiquitin-like proteins facilitates enzymatic turnover. EMBO J. 21, 1456–1464 (2002). This work shows that cycles of SUMO modification and demodification of TDG contribute to the enzyme's function, most likely through conformational changes that allow product release and rebinding (see also reference 98).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. Baba, D. et al. Crystal structure of thymine DNA glycosylase conjugated to SUMO-1. Nature 435, 979–982 (2005).

    CAS  PubMed  Article  Google Scholar 

  99. Minty, A., Dumont, X., Kaghad, M. & Caput, D. Covalent modification of p73α by SUMO-1. J. Biol. Chem. 275, 36316–36323 (2000).

    CAS  PubMed  Article  Google Scholar 

  100. Song, J., Durrin, L. K., Wilkinson, T. A., Krontiris, T. G. & Chen, Y. Identification of a SUMO-binding motif that recognizes SUMO-modified proteins. Proc. Natl Acad. Sci. USA 101, 14373–14378 (2004). Through NMR analysis of a PIAS peptide, previously shown to bind SUMO non-covalently (see reference 99), the authors define a minimal SUMO-binding motif.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  101. Hecker, C. M., Rabiller, M., Haglund, K., Bayer, P. & Dikic, I. Specification of SUMO1- and SUMO2-interacting motifs. J. Biol. Chem. 281, 16117–16127 (2006).

    CAS  PubMed  Article  Google Scholar 

  102. Hannich, J. T. et al. Defining the SUMO-modified proteome by multiple approaches in Saccharomyces cerevisiae. J. Biol. Chem. 280, 4102–4110 (2005).

    CAS  PubMed  Article  Google Scholar 

  103. Song, J., Zhang, Z., Hu, W. & Chen, Y. Small ubiquitin-like modifier (SUMO) recognition of a SUMO binding motif: a reversal of the bound orientation. J. Biol. Chem. 280, 40122–40129 (2005).

    CAS  PubMed  Article  Google Scholar 

  104. Shen, T. H., Lin, H. K., Scaglioni, P. P., Yung, T. M. & Pandolfi, P. P. The mechanisms of PML-nuclear body formation. Mol. Cell 24, 331–339 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. Lin, D. Y. et al. Role of SUMO-interacting motif in Daxx SUMO modification, subnuclear localization, and repression of sumoylated transcription factors. Mol. Cell 24, 341–354 (2006). Non-covalent interaction of Daxx with SUMO is required for Daxx-dependent transcriptional repression as well as for Daxx sumoylation.

    CAS  PubMed  Article  Google Scholar 

  106. Kuo, H. Y. et al. SUMO modification negatively modulates the transcriptional activity of CREB-binding protein via the recruitment of Daxx. Proc. Natl Acad. Sci. USA 102, 16973–16978 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  107. Prudden, J. et al. SUMO-targeted ubiquitin ligases in genome stability. EMBO J. 26, 4089–4101 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. Sun, H., Leverson, J. D. & Hunter, T. Conserved function of RNF4 family proteins in eukaryotes: targeting a ubiquitin ligase to SUMOylated proteins. EMBO J. 26, 4102–4112 (2007). This paper, together with references 107, 109 and 110, suggests that SUMO can serve as a degradation signal by recruiting a ubiquitin E3 ligase via a non-covalent SUMO–SIM/SBM interaction with its targets.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. Uzunova, K. et al. Ubiquitin-dependent proteolytic control of SUMO conjugates. J. Biol. Chem. 29 Aug 2007 (doi:10.1074/jbc.M706505200).

    CAS  Article  Google Scholar 

  110. Xie, Y. et al. The yeast HEX3–SLX8 heterodimer is a ubiquitin ligase stimulated by substrate sumoylation. J. Biol. Chem. 11 Sep 2007 (doi:10.1074/jbc.M706025200).

    CAS  Article  Google Scholar 

  111. Hicke, L., Schubert, H. L. & Hill, C. P. Ubiquitin-binding domains. Nature Rev. Mol. Cell Biol. 6, 610–621 (2005).

    CAS  Article  Google Scholar 

  112. Chupreta, S., Holmstrom, S., Subramanian, L. & Iniguez-Lluhi, J. A. A small conserved surface in SUMO is the critical structural determinant of its transcriptional inhibitory properties. Mol. Cell. Biol. 25, 4272–4282 (2005). Extensive analysis of SUMO2 mutants revealed a surface in SUMO strictly that is required for transcriptional repression. This surface is now known to interact with SIM/SBM.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. Yang, S. H. & Sharrocks, A. D. SUMO promotes HDAC-mediated transcriptional repression. Mol. Cell 13, 611–617 (2004).

    CAS  PubMed  Article  Google Scholar 

  114. Lin, D. Y. et al. Negative modulation of androgen receptor transcriptional activity by Daxx. Mol. Cell. Biol. 24, 10529–10541 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. Hay, R. T. SUMO: a history of modification. Mol. Cell 18, 1–12 (2005).

    CAS  PubMed  Article  Google Scholar 

  116. Bossis, G. et al. Down-regulation of c-Fos/c-Jun AP-1 dimer activity by sumoylation. Mol. Cell. Biol. 25, 6964–6979 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. Lin, J. Y., Ohshima, T. & Shimotohno, K. Association of Ubc9, an E2 ligase for SUMO conjugation, with p53 is regulated by phosphorylation of p53. FEBS Lett. 573, 15–18 (2004).

    CAS  PubMed  Article  Google Scholar 

  118. Ross, S., Best, J. L., Zon, L. I. & Gill, G. SUMO-1 modification represses Sp3 transcriptional activation and modulates its subnuclear localization. Mol. Cell 10, 831–842 (2002).

    CAS  PubMed  Article  Google Scholar 

  119. Stelter, P. & Ulrich, H. D. Control of spontaneous and damage-induced mutagenesis by SUMO and ubiquitin conjugation. Nature 425, 188–191 (2003).

    CAS  Article  PubMed  Google Scholar 

  120. Ulrich, H. D. Mutual interactions between the SUMO and ubiquitin systems: a plea of no contest. Trends Cell Biol. 15, 525–532 (2005).

    CAS  PubMed  Article  Google Scholar 

  121. Mabb, A. M., Wuerzberger-Davis, S. M. & Miyamoto, S. PIASy mediates NEMO sumoylation and NF-κB activation in response to genotoxic stress. Nature Cell Biol. 8, 986–993 (2006).

    CAS  PubMed  Article  Google Scholar 

  122. Huang, T. T., Wuerzberger-Davis, S. M., Wu, Z. H. & Miyamoto, S. Sequential modification of NEMO/IKKγ by SUMO-1 and ubiquitin mediates NF-κB activation by genotoxic stress. Cell 115, 565–576 (2003).

    CAS  Article  PubMed  Google Scholar 

  123. Shalizi, A. et al. A calcium-regulated MEF2 sumoylation switch controls postsynaptic differentiation. Science 311, 1012–1017 (2006).

    CAS  PubMed  Article  Google Scholar 

  124. Johnson, E. S. & Blobel, G. Cell cycle-regulated attachment of the ubiquitin-related protein SUMO to the yeast septins. J. Cell Biol. 147, 981–994 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. Lee, Y. J. et al. Protein SUMOylation is massively increased in hibernation torpor and is critical for the cytoprotection provided by ischemic preconditioning and hypothermia in SHSY5Y cells. J. Cereb. Blood Flow Metab. 27, 950–962 (2007).

    CAS  PubMed  Article  Google Scholar 

  126. Kurepa, J. et al. The small ubiquitin-like modifier (SUMO) protein modification system in Arabidopsis. Accumulation of SUMO1 and -2 conjugates is increased by stress. J. Biol. Chem. 278, 6862–6872 (2003).

    CAS  PubMed  Article  Google Scholar 

  127. Bossis, G. & Melchior, F. Regulation of SUMOylation by reversible oxidation of SUMO conjugating enzymes. Mol. Cell 21, 349–357 (2006). Depending on the dose, H 2 O 2 can cause global or local loss of sumoylation due to reversible crosslinking of SUMO E1 and E2 enzymes.

    CAS  Article  PubMed  Google Scholar 

  128. Boggio, R., Colombo, R., Hay, R. T., Draetta, G. F. & Chiocca, S. A mechanism for inhibiting the SUMO pathway. Mol. Cell 16, 549–561 (2004).

    CAS  PubMed  Article  Google Scholar 

  129. Boggio, R., Passafaro, A. & Chiocca, S. Targeting SUMO E1 to ubiquitin ligases: a viral strategy to counteract sumoylation. J. Biol. Chem. 282, 15376–15382 (2007). The viral protein Gam1 abolishes global sumoylation by targeting SUMO E1 for ubiquitin-mediated degradation (together with reference 128).

    CAS  PubMed  Article  Google Scholar 

  130. Cheng, J., Bawa, T., Lee, P., Gong, L. & Yeh, E. T. Role of desumoylation in the development of prostate cancer. Neoplasia 8, 667–676 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. Mo, Y. Y., Yu, Y., Theodosiou, E., Rachel Ee, P. L. & Beck, W. T. A role for Ubc9 in tumorigenesis. Oncogene 24, 2677–2683 (2005).

    CAS  PubMed  Article  Google Scholar 

  132. Harder, Z., Zunino, R. & McBride, H. Sumo1 conjugates mitochondrial substrates and participates in mitochondrial fission. Curr. Biol. 14, 340–345 (2004).

    CAS  PubMed  Article  Google Scholar 

  133. Dadke, S. et al. Regulation of protein tyrosine phosphatase 1B by sumoylation. Nature Cell Biol. 9, 80–85 (2007). The ER-associated PTP1B is a SUMO target. In vitro assays suggest that sumoylation directly inactivates the enzyme.

    CAS  PubMed  Article  Google Scholar 

  134. Rajan, S., Plant, L. D., Rabin, M. L., Butler, M. H. & Goldstein, S. A. Sumoylation silences the plasma membrane leak K+ channel K2P1. Cell 121, 37–47 (2005).

    CAS  PubMed  Article  Google Scholar 

  135. Feliciangeli, S. et al. Does sumoylation control K2P1/TWIK1 background K+ channels? Cell 130, 563–569 (2007).

    CAS  PubMed  Article  Google Scholar 

  136. Benson, M. D. et al. SUMO modification regulates inactivation of the voltage-gated potassium channel Kv1.5. Proc. Natl Acad. Sci. USA 104, 1805–1810 (2007). A voltage-gated potassium channel is a target for reversible sumoylation.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  137. Wible, B. A., Yang, Q., Kuryshev, Y. A., Accili, E. A. & Brown, A. M. Cloning and expression of a novel K+ channel regulatory protein, KChAP. J. Biol. Chem. 273, 11745–11751 (1998).

    CAS  PubMed  Article  Google Scholar 

  138. Tang, Z., El Far, O., Betz, H. & Scheschonka, A. Pias1 interaction and sumoylation of metabotropic glutamate receptor 8. J. Biol. Chem. 280, 38153–38159 (2005).

    CAS  PubMed  Article  Google Scholar 

  139. Martin, S., Nishimune, A., Mellor, J. R. & Henley, J. M. SUMOylation regulates kainate-receptor-mediated synaptic transmission. Nature 447, 321–325 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  140. Seeler, J. S., Bischof, O., Nacerddine, K. & Dejean, A. SUMO, the three Rs and cancer. Curr. Top. Microbiol. Immunol. 313, 49–71 (2007).

    CAS  PubMed  Google Scholar 

  141. Dorval, V. & Fraser, P. E. SUMO on the road to neurodegeneration. Biochim. Biophys. Acta 1773, 694–706 (2007).

    CAS  PubMed  Article  Google Scholar 

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Acknowledgements

We would like to thank all laboratory members for very enjoyable discussions and helpful comments. We are especially grateful for suggestions by the anonymous reviewers. The authors would like to acknowledge support by the EU network Rubicon and by the Deutsche Forschungsgemeinschaft (DFG). Finally, we apologize for all the important papers that could not be cited due to space limitations.

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Correspondence to Frauke Melchior.

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Saccharomyces cerevisiae proteins of the SUMO pathway (PDF 167 kb)

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Human proteins of the SUMO pathway (PDF 217 kb)

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Glossary

SUMO-interaction/binding motif

A short motif in proteins that mediates non-covalent interaction with SUMO. This motif is characterized as hxhh or hhxh (in which h is Val, Ile or Leu and x is any amino acid), flanked by acidic amino acids, and in some cases by Ser residues.

E1 activating enzyme

An enzyme that forms a high-energy bond (thioester) with the C-terminal Gly residue of ubiquitin or a ubiquitin-like protein in an ATP-dependent reaction.

E2 conjugating enzyme

An enzyme that accepts ubiquitin or a ubiquitin-like protein from an E1 enzyme and transfers it to a substrate protein via the formation of an isopeptide bond. This step usually requires cooperation with an E3 ligase.

E3 ligase

An enzyme that facilitates the transfer of ubiquitin or ubiquitin-like protein from an E2 enzyme to a substrate protein. Ubiquitin HECT E3 ligases form thioester intermediates with ubiquitin, whereas all other known E3 ligases form complexes with the thioester-charged E2 and the target.

SP-RING motif

A RING-related sequence (Sx2Cx15CxHx2C/Sx17Cx2C (in which x is any amino acid)) that is predicted to have a RING-like structure.

RING domain

A sequence of Cys and His residues that binds two zinc cations: Cx2Cx(9–39)Cx(1–3)Hx(2–3)C/Hx2C/x(4–48)Cx2C (in which x is any amino acid).

PIAS family

A group of SUMO E3 ligases, initially identified for their ability to repress the transcription factor STAT3 (PIAS: protein inhibitors of activated STAT). All PIAS proteins share a SAP domain (which binds nucleic acids), an SPRING and a SUMO-interaction/binding motif.

Polycomb group (PcG) proteins

A family of proteins, originally described in Drosophila melanogaster, that maintains the stable and heritable repression of several genes, including the homeotic genes.

Sentrin-specific proteases

(SENPs). Mammalian Cys proteases related to Saccharomyces cerevisiae Ulp1 and Ulp2. Like their yeast counterparts, most SENPs are SUMO-specific isopeptidases and C-terminal hydrolases (SENP8 is an exception).

Nuclear pore complex

(NPC). A macromolecular protein complex that is embedded in the nuclear envelope. NPCs allow the exchange of ions, metabolites and macromolecules between the nucleus and the cytoplasm.

SUMO-acceptor site

The Lys residue in a target to which SUMO is coupled. It is frequently found in the sequence motif ΨKxE (in which Ψ is a bulky aliphatic amino acid and x is any amino acid).

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Geiss-Friedlander, R., Melchior, F. Concepts in sumoylation: a decade on. Nat Rev Mol Cell Biol 8, 947–956 (2007). https://doi.org/10.1038/nrm2293

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