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An additional role for SUMO in ubiquitin-mediated proteolysis

Nature Reviews Molecular Cell Biology volume 10, pages 564–568 (2009)Cite this article

Abstract

Although the post-translational modification of proteins with small ubiquitin-like modifier (SUMO) has a role in many biological processes, it was thought that SUMO, unlike ubiquitin, does not target proteins for degradation. However, these views need to be revised, as recent findings in yeast and human cells indicate that SUMO can act as a signal for the recruitment of E3 ubiquitin ligases, which leads to the ubiquitylation and degradation of the modified protein.

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Figure 1: SUMO-dependent ubiquitin E3 ligases.
Figure 2: Model for RNF4-dependent degradation.

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References

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

    Article  CAS  PubMed  Google Scholar 

  2. Ikeda, F. & Dikic, I. Atypical ubiquitin chains: new molecular signals. 'Protein Modifications: Beyond the Usual Suspects' review series. EMBO Rep. 9, 536–542 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 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).

    Article  CAS  PubMed  Google Scholar 

  4. 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).

    Article  CAS  PubMed  Google Scholar 

  5. Rodriguez, M. S., Dargemont, C. & Hay, R. T. SUMO-1 conjugation in vivo requires both a consensus modification motif and nuclear targeting. J. Biol. Chem. 276, 12654–12659 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Hay, R. T. SUMO-specific proteases: a twist in the tail. Trends Cell Biol. 17, 370–376 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. 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).

    Article  CAS  PubMed  Google Scholar 

  8. Evdokimov, E., Sharma, P., Lockett, S. J., Lualdi, M. & Kuehn, M. R. Loss of SUMO1 in mice affects RanGAP1 localization and formation of PML nuclear bodies, but is not lethal as it can be compensated by SUMO2 or SUMO3. J. Cell Sci. 121, 4106–4113 (2008).

    Article  CAS  PubMed  Google Scholar 

  9. Zhang, F. P. et al. Sumo-1 function is dispensable in normal mouse development. Mol. Cell. Biol. 28, 5381–5390 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. 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).

    Article  CAS  PubMed  Google Scholar 

  12. Johnson, E. S. & Gupta, A. A. An E3-like factor that promotes SUMO conjugation to the yeast septins. Cell 106, 735–744 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Matic, I. et al. In vivo identification of human small ubiquitin-like modifier polymerization sites by high accuracy mass spectrometry and an in vitro to in vivo strategy. Mol. Cell Proteomics 7, 132–144 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. 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).

    Article  CAS  PubMed  Google Scholar 

  15. 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).

    Article  CAS  PubMed  Google Scholar 

  16. Mullen, J. R., Kaliraman, V., Ibrahim, S. S. & Brill, S. J. Requirement for three novel protein complexes in the absence of the Sgs1 DNA helicase in Saccharomyces cerevisiae. Genetics 157, 103–118 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Wang, Z., Jones, G. M. & Prelich, G. Genetic analysis connects SLX5 and SLX8 to the SUMO pathway in Saccharomyces cerevisiae. Genetics 172, 1499–1509 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Xie, Y. et al. The yeast Hex3˙Slx8 heterodimer is a ubiquitin ligase stimulated by substrate sumoylation. J. Biol. Chem. 282, 34176–34184 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Uzunova, K. et al. Ubiquitin-dependent proteolytic control of SUMO conjugates. J. Biol. Chem. 282, 34167–34175 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kosoy, A., Calonge, T. M., Outwin, E. A. & O'Connell, M. J. Fission yeast Rnf4 homologs are required for DNA repair. J. Biol. Chem. 282, 20388–20394 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Li, T., Fung, J., Mullen, J. R. & Brill, S. J. The yeast Slx5–Slx8 DNA integrity complex displays ubiquitin ligase activity. Cell Cycle 6, 2800–2809 (2007).

    Article  Google Scholar 

  24. Mullen, J. R. & Brill, S. J. Activation of the SLX5–SLX8 ubiquitin ligase by poly-SUMO conjugates. J. Biol. Chem. 283, 19912–19921 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Nagai, S. et al. Functional targeting of DNA damage to a nuclear pore-associated SUMO-dependent ubiquitin ligase. Science 322, 597–602 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang, Z. & Prelich, G. Quality control of a transcriptional regulator by SUMO-targeted degradation. Mol. Cell. Biol. 29, 1694–1706 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Li, W. et al. Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling. PLoS ONE 3, e1487 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Moilanen, A. M. et al. Identification of a novel RING finger protein as a coregulator in steroid receptor-mediated gene transcription. Mol. Cell. Biol. 18, 5128–5139 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chiariotti, L. et al. Identification and characterization of a novel RING-finger gene (RNF4) mapping at 4p16.3. Genomics 47, 258–265 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Hakli, M., Karvonen, U., Janne, O. A. & Palvimo, J. J. SUMO-1 promotes association of SNURF (RNF4) with PML nuclear bodies. Exp. Cell Res. 304, 224–233 (2005).

    Article  PubMed  Google Scholar 

  31. Tatham, M. H. et al. RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nature Cell Biol. 10, 538–546 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Bailey, D. & O'Hare, P. Comparison of the SUMO1 and ubiquitin conjugation pathways during the inhibition of proteasome activity with evidence of SUMO1 recycling. Biochem. J. 392, 271–281 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sardiello, M., Cairo, S., Fontanella, B., Ballabio, A. & Meroni, G. Genomic analysis of the TRIM family reveals two groups of genes with distinct evolutionary properties. BMC Evol. Biol. 8, 225 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  34. de The, H., Chomienne, C., Lanotte, M., Degos, L. & Dejean, A. The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor α gene to a novel transcribed locus. Nature 347, 558–561 (1990).

    Article  CAS  PubMed  Google Scholar 

  35. de The, H. et al. The PML–RARα fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell 66, 675–684 (1991).

    Article  CAS  PubMed  Google Scholar 

  36. Kakizuka, A. et al. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RARα with a novel putative transcription factor, PML. Cell 66, 663–674 (1991).

    Article  CAS  PubMed  Google Scholar 

  37. Wang, Z. Y. & Chen, Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood 111, 2505–2515 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Maul, G. G., Negorev, D., Bell, P. & Ishov, A. M. Review: properties and assembly mechanisms of ND10, PML bodies, or PODs. J. Struct. Biol. 129, 278–287 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Lallemand-Breitenbach, V. et al. Arsenic degrades PML or PML–RARα through a SUMO-triggered RNF4/ubiquitin-mediated pathway. Nature Cell Biol. 10, 547–555 (2008).

    Article  CAS  PubMed  Google Scholar 

  40. Boddy, M. N., Howe, K., Etkin, L. D., Solomon, E. & Freemont, P. S. PIC 1, 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 

  41. Duprez, E. et al. SUMO-1 modification of the acute promyelocytic leukaemia protein PML: implications for nuclear localisation. J. Cell Sci. 112, 381–393 (1999).

    CAS  PubMed  Google Scholar 

  42. Ishov, A. M. et al. PML is critical for ND10 formation and recruits the PML-interacting protein Daxx to this nuclear structure when modified by SUMO-1. J. Cell Biol. 147, 221–234 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kamitani, T., Nguyen, H. P., Kito, K., Fukuda-Kamitani, T. & Yeh, E. T. Covalent modification of PML by the sentrin family of ubiquitin-like proteins. J. Biol. Chem. 273, 3117–3120 (1998).

    Article  CAS  PubMed  Google Scholar 

  44. Lallemand-Breitenbach, V. et al. Role of promyelocytic leukemia (PML) sumolation in nuclear body formation, 11S proteasome recruitment, and As2O3-induced PML or PML/retinoic acid receptor α degradation. J. Exp. Med. 193, 1361–1371 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sobko, A., Ma, H. & Firtel, R. A. Regulated SUMOylation and ubiquitination of DdMEK1 is required for proper chemotaxis. Dev. Cell 2, 745–756 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Shyu, H. W., Hsu, S. H., Hsieh-Li, H. M. & Li, H. Forced expression of RNF36 induces cell apoptosis. Exp. Cell Res. 287, 301–313 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Cheng, J., Kang, X., Zhang, S. & Yeh, E. T. SUMO-specific protease 1 is essential for stabilization of HIF1α during hypoxia. Cell 131, 584–595 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bae, S. H. et al. Sumoylation increases HIF-1α stability and its transcriptional activity. Biochem. Biophys. Res. Commun. 324, 394–400 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Carbia-Nagashima, A. et al. RSUME, a small RWD-containing protein, enhances SUMO conjugation and stabilizes HIF-1α during hypoxia. Cell 131, 309–323 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Li, T., Mullen, J. R., Slagle, C. E. & Brill, S. J. Stimulation of in vitro sumoylation by Slx5–Slx8: evidence for a functional interaction with the SUMO pathway. DNA Repair (Amst.) 6, 1679–1691 (2007).

    Article  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lima, C. D. & Reverter, D. Structure of the human SENP7 catalytic domain and poly-SUMO deconjugation activities for SENP6 and SENP7. J. Biol. Chem. 283, 32045–32055 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Muller, S., Miller, W. H. Jr. & Dejean, A. Trivalent antimonials induce degradation of the PML–RAR oncoprotein and reorganization of the promyelocytic leukemia nuclear bodies in acute promyelocytic leukemia NB4 cells. Blood 92, 4308–4316 (1998).

    CAS  PubMed  Google Scholar 

  54. Davison, K., Mann, K. K., Waxman, S. & Miller, W. H. Jr. JNK activation is a mediator of arsenic trioxide-induced apoptosis in acute promyelocytic leukemia cells. Blood 103, 3496–3502 (2004).

    Article  CAS  PubMed  Google Scholar 

  55. Hayakawa, F. & Privalsky, M. L. Phosphorylation of PML by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis. Cancer Cell 5, 389–401 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Verma, A. et al. Activation of the p38 mitogen-activated protein kinase mediates the suppressive effects of type I interferons and transforming growth factor-β on normal hematopoiesis. J. Biol. Chem. 277, 7726–7735 (2002).

    Article  CAS  PubMed  Google Scholar 

  57. Joe, Y. et al. ATR, PML, and CHK2 play a role in arsenic trioxide-induced apoptosis. J. Biol. Chem. 281, 28764–28771 (2006).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

M.C.G. is supported by a fellowship from the RUBICON European Union FP6 Network of Excellence. Work in the R.T.H. laboratory is supported by Cancer Research UK, the Medical Research Council and the Biotechnology and Biological Sciences Research Council.

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  1. Marie-Claude Geoffroy and Ronald T. Hay are at the Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, UK.,

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Correspondence to Ronald T. Hay.

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Geoffroy, MC., Hay, R. An additional role for SUMO in ubiquitin-mediated proteolysis. Nat Rev Mol Cell Biol 10, 564–568 (2009). https://doi.org/10.1038/nrm2707

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