SUMOylation (Homo sapiens)

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1, 7, 17, 22, 35...15, 19, 20, 25, 27...5, 249, 10, 24, 26, 375, 246, 9, 11, 23, 24, 26...15, 19, 20, 25, 27...5, 245, 2415, 19, 20, 25, 27...nucleoplasmcytosolPPiUBE2IAMPSUMO2:UBE2ISUMO3(1-103)SUMO2(1-95)UBA2 SUMO2ATPSENP5 UBE2ISUMO3:UBE2IAMPSUMO1SUMO2-C173-UBA2 SUMO3:UBA2:SAE1SUMO1-C173-UBA2 SUMO1:UBA2:SAE1SENP1 SUMO2:UBA2:SAE1UBA2-G93-SUMO2 SUMO3SUMO1:C93-UBE2IATPSUMO E3 ligasesSUMOylate targetproteinsSENP2 UBA2:SAE1UBA2 UBA2:SAE1SUMO1(2-101)SAE1 SUMO3-C173-UBA2 UBE2IUBA2-G97-SUMO1 SENP1,2,5AMPUBA2:SAE1UBA2-G92-SUMO3 SAE1 SAE1 PPiPPiUBA2 SAE1 SAE1 SAE1 ATP3, 13222220, 25, 3022222223, 13233221322222131, 4, 8, 12, 14...232


Description

Small Ubiquitin-like MOdifiers (SUMOs) are a family of 3 proteins (SUMO1,2,3) that are reversibly conjugated to lysine residues of target proteins via a glycine-lysine isopeptide bond (reviewed in Hay 2013, Hannoun et al. 2010, Gareau and Lima 2010, Wilkinson and Henley 2010, Wang and Dasso 2009). Proteomic methods have yielded estimates of hundreds of target proteins. Targets are mostly located in the nucleus and therefore SUMOylation disproportionately affects gene expression.
SUMOs are initially translated as proproteins possessing extra amino acid residues at the C-terminus which are removed by the SUMO processing endoproteases SENP1,2,5 (Hay 2007). Different SENPs have significantly different efficiencies with different SUMOs. The processing exposes a glycine residue at the C-terminus that is activated by ATP-dependent thiolation at cysteine-173 of UBA2 in a complex with SAE1, the E1 complex. The SUMO is transferred from E1 to cysteine-93 of a single E2 enzyme, UBC9 (UBE2I). UBC9 with or, in some cases, without an E3 ligase conjugates the glycine C-terminus of SUMO to an epsilon amino group of a lysine residue on the target protein. SUMO2 and SUMO3 may then be further polymerized, forming chains. SUMO1 is unable to form polymers.
Conjugated SUMO can act as a biinding site for proteins possessing SUMO interaction motifs (SIMs) and can also directly affect the formation of complexes between the target protein and other proteins.
Conjugated SUMOs are removed by cleavage of the isopeptide bond by processing enzymes SENP1,2,3,5. The processing enzymes SENP6 and SENP7 edit chains of SUMO2 and SUMO3. View original pathway at:Reactome.

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Bibliography

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  1. Lois LM, Lima CD.; ''Structures of the SUMO E1 provide mechanistic insights into SUMO activation and E2 recruitment to E1.''; PubMed Europe PMC Scholia
  2. Golebiowski F, Matic I, Tatham MH, Cole C, Yin Y, Nakamura A, Cox J, Barton GJ, Mann M, Hay RT.; ''System-wide changes to SUMO modifications in response to heat shock.''; PubMed Europe PMC Scholia
  3. Wang Y, Dasso M.; ''SUMOylation and deSUMOylation at a glance.''; PubMed Europe PMC Scholia
  4. Hay RT.; ''SUMO-specific proteases: a twist in the tail.''; PubMed Europe PMC Scholia
  5. Zhang H, Saitoh H, Matunis MJ.; ''Enzymes of the SUMO modification pathway localize to filaments of the nuclear pore complex.''; PubMed Europe PMC Scholia
  6. Wang J, Chen Y.; ''Role of the Zn(2+) motif of E1 in SUMO adenylation.''; PubMed Europe PMC Scholia
  7. Tatham MH, Chen Y, Hay RT.; ''Role of two residues proximal to the active site of Ubc9 in substrate recognition by the Ubc9.SUMO-1 thiolester complex.''; PubMed Europe PMC Scholia
  8. Wilkinson KA, Henley JM.; ''Mechanisms, regulation and consequences of protein SUMOylation.''; PubMed Europe PMC Scholia
  9. Desterro JM, Rodriguez MS, Kemp GD, Hay RT.; ''Identification of the enzyme required for activation of the small ubiquitin-like protein SUMO-1.''; PubMed Europe PMC Scholia
  10. Werner A, Moutty MC, Möller U, Melchior F.; ''Performing in vitro sumoylation reactions using recombinant enzymes.''; PubMed Europe PMC Scholia
  11. Di Bacco A, Ouyang J, Lee HY, Catic A, Ploegh H, Gill G.; ''The SUMO-specific protease SENP5 is required for cell division.''; PubMed Europe PMC Scholia
  12. Kim YH, Sung KS, Lee SJ, Kim YO, Choi CY, Kim Y.; ''Desumoylation of homeodomain-interacting protein kinase 2 (HIPK2) through the cytoplasmic-nuclear shuttling of the SUMO-specific protease SENP1.''; PubMed Europe PMC Scholia
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  14. Bailey D, O'Hare P.; ''Characterization of the localization and proteolytic activity of the SUMO-specific protease, SENP1.''; PubMed Europe PMC Scholia
  15. Yang XJ, Chiang CM.; ''Sumoylation in gene regulation, human disease, and therapeutic action.''; PubMed Europe PMC Scholia
  16. Jentsch S, Psakhye I.; ''Control of nuclear activities by substrate-selective and protein-group SUMOylation.''; PubMed Europe PMC Scholia
  17. Da Silva-Ferrada E, Lopitz-Otsoa F, Lang V, Rodríguez MS, Matthiesen R.; ''Strategies to Identify Recognition Signals and Targets of SUMOylation.''; PubMed Europe PMC Scholia
  18. Kamitani T, Kito K, Nguyen HP, Fukuda-Kamitani T, Yeh ET.; ''Characterization of a second member of the sentrin family of ubiquitin-like proteins.''; PubMed Europe PMC Scholia
  19. Becker J, Barysch SV, Karaca S, Dittner C, Hsiao HH, Berriel Diaz M, Herzig S, Urlaub H, Melchior F.; ''Detecting endogenous SUMO targets in mammalian cells and tissues.''; PubMed Europe PMC Scholia
  20. Zhao J.; ''Sumoylation regulates diverse biological processes.''; PubMed Europe PMC Scholia
  21. Tatham MH, Matic I, Mann M, Hay RT.; ''Comparative proteomic analysis identifies a role for SUMO in protein quality control.''; PubMed Europe PMC Scholia
  22. Gong L, Millas S, Maul GG, Yeh ET.; ''Differential regulation of sentrinized proteins by a novel sentrin-specific protease.''; PubMed Europe PMC Scholia
  23. Mikolajczyk J, Drag M, Békés M, Cao JT, Ronai Z, Salvesen GS.; ''Small ubiquitin-related modifier (SUMO)-specific proteases: profiling the specificities and activities of human SENPs.''; PubMed Europe PMC Scholia
  24. Okuma T, Honda R, Ichikawa G, Tsumagari N, Yasuda H.; ''In vitro SUMO-1 modification requires two enzymatic steps, E1 and E2.''; PubMed Europe PMC Scholia
  25. Itahana Y, Yeh ET, Zhang Y.; ''Nucleocytoplasmic shuttling modulates activity and ubiquitination-dependent turnover of SUMO-specific protease 2.''; PubMed Europe PMC Scholia
  26. Wang J, Lee B, Cai S, Fukui L, Hu W, Chen Y.; ''Conformational transition associated with E1-E2 interaction in small ubiquitin-like modifications.''; PubMed Europe PMC Scholia
  27. Bruderer R, Tatham MH, Plechanovova A, Matic I, Garg AK, Hay RT.; ''Purification and identification of endogenous polySUMO conjugates.''; PubMed Europe PMC Scholia
  28. Xu Z, Au SW.; ''Mapping residues of SUMO precursors essential in differential maturation by SUMO-specific protease, SENP1.''; PubMed Europe PMC Scholia
  29. Gong L, Yeh ET.; ''Characterization of a family of nucleolar SUMO-specific proteases with preference for SUMO-2 or SUMO-3.''; PubMed Europe PMC Scholia
  30. Hang J, Dasso M.; ''Association of the human SUMO-1 protease SENP2 with the nuclear pore.''; PubMed Europe PMC Scholia
  31. Su HL, Li SS.; ''Molecular features of human ubiquitin-like SUMO genes and their encoded proteins.''; PubMed Europe PMC Scholia
  32. Gareau JR, Lima CD.; ''The SUMO pathway: emerging mechanisms that shape specificity, conjugation and recognition.''; PubMed Europe PMC Scholia
  33. Hay RT.; ''Decoding the SUMO signal.''; PubMed Europe PMC Scholia
  34. Flotho A, Melchior F.; ''Sumoylation: a regulatory protein modification in health and disease.''; PubMed Europe PMC Scholia
  35. Tatham MH, Jaffray E, Vaughan OA, Desterro JM, Botting CH, Naismith JH, Hay RT.; ''Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9.''; PubMed Europe PMC Scholia
  36. Hannoun Z, Greenhough S, Jaffray E, Hay RT, Hay DC.; ''Post-translational modification by SUMO.''; PubMed Europe PMC Scholia
  37. Citro S, Chiocca S.; ''Sumo paralogs: redundancy and divergencies.''; PubMed Europe PMC Scholia
  38. Vertegaal AC, Andersen JS, Ogg SC, Hay RT, Mann M, Lamond AI.; ''Distinct and overlapping sets of SUMO-1 and SUMO-2 target proteins revealed by quantitative proteomics.''; PubMed Europe PMC Scholia
  39. Wang J, Hu W, Cai S, Lee B, Song J, Chen Y.; ''The intrinsic affinity between E2 and the Cys domain of E1 in ubiquitin-like modifications.''; PubMed Europe PMC Scholia
  40. Azuma Y, Tan SH, Cavenagh MM, Ainsztein AM, Saitoh H, Dasso M.; ''Expression and regulation of the mammalian SUMO-1 E1 enzyme.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114754view16:24, 25 January 2021ReactomeTeamReactome version 75
113198view11:26, 2 November 2020ReactomeTeamReactome version 74
112423view15:36, 9 October 2020ReactomeTeamReactome version 73
101327view11:21, 1 November 2018ReactomeTeamreactome version 66
100865view20:54, 31 October 2018ReactomeTeamreactome version 65
100406view19:28, 31 October 2018ReactomeTeamreactome version 64
99954view16:12, 31 October 2018ReactomeTeamreactome version 63
99510view14:45, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99154view12:41, 31 October 2018ReactomeTeamreactome version 62
94055view13:54, 16 August 2017ReactomeTeamreactome version 61
93683view11:31, 9 August 2017ReactomeTeamreactome version 61
88416view11:53, 5 August 2016FehrhartOntology Term : 'sumoylation pathway' added !
86807view09:26, 11 July 2016ReactomeTeamreactome version 56
83213view10:24, 18 November 2015ReactomeTeamVersion54
81603view13:08, 21 August 2015ReactomeTeamVersion53
77059view08:36, 17 July 2014ReactomeTeamFixed remaining interactions
76764view12:12, 16 July 2014ReactomeTeamFixed remaining interactions
76088view10:15, 11 June 2014ReactomeTeamRe-fixing comment source
75799view11:33, 10 June 2014ReactomeTeamReactome 48 Update
75150view14:09, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74797view08:53, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
AMPMetaboliteCHEBI:16027 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
PPiMetaboliteCHEBI:29888 (ChEBI)
SAE1 ProteinQ9UBE0 (Uniprot-TrEMBL)
SENP1 ProteinQ9P0U3 (Uniprot-TrEMBL)
SENP1,2,5ComplexR-HSA-2990834 (Reactome)
SENP2 ProteinQ9HC62 (Uniprot-TrEMBL)
SENP5 ProteinQ96HI0 (Uniprot-TrEMBL)
SUMO E3 ligases

SUMOylate target

proteins		PathwayR-HSA-3108232 (Reactome) SUMO proteins are conjugated to lysine residues of target proteins via an isopeptide bond with the C-terminal glycine of SUMO (reviewed in Zhao 2007, Gareau and Lima 2010, Hannoun et al. 2010, Citro and Chiocca 2013, Yang and Chiang 2013). Proteomic analyses indicate that SUMO is conjugated to hundreds of proteins and most targets of SUMOylation are nuclear (Vertegal et al. 2006, Bruderer et al. 2011, Tatham et al. 2011, Da Silva et al. 2012, Becker et al. 2013).
UBE2I (UBC9), the E2 activating enzyme of the SUMO pathway, is itself also a SUMO E3 ligase. Most SUMOylation reactions will proceed with only the substrate protein and the UBE2I:SUMO thioester conjugate. The rates of some reactions are further enhanced by the action of other E3 ligases such as RANBP2. These E3 ligases catalyze SUMO transfer to substrate by one of two basic mechanisms: they interact with both the substrate and UBE2I:SUMO thus bringing them into proximity or they enhance the release of SUMO from UBE2I to the substrate.
Most SUMOylation reactions occur in the nucleoplasm therefore most targets of SUMOylation are nuclear proteins such as transcription factors, transcription cofactors, and nuclear receptors. In the cell SUMO1 is mainly concentrated at the nuclear membrane and in nuclear bodies. Most SUMO1 is conjugated to RANGAP1 near the nuclear pore. SUMO2 is at least partially cytosolic and SUMO3 is located mainly in nuclear bodies. Most SUMO2 and SUMO3 is unconjugated in unstressed cells and becomes conjugated to target proteins in response to stress (Golebiowski et al. 2009). Especially notable is the requirement for recruitment of SUMO to sites of DNA damage where conjugation to targets seems to coordinate the repair process (Flotho and Melchior 2013).
Several effects of SUMOylation have been described: steric interference with protein-protein interactions, interference with other post-translational modifications such as ubiquitinylation and phosphorylation, and recruitment of proteins that possess a SUMO-interacting motif (SIM) (reviewed in Zhao 2007, Flotho and Melchior 2013, Jentsch and Psakhye 2013, Yang and Chiang 2013). In most cases SUMOylation inhibits the activity of the target protein.
The SUMOylation reactions included in this module have met two criteria: They have been verified by assays of individual proteins (as opposed to mass proteomic assays) and the effect of SUMOylation on the function of the target protein has been tested.
SUMO1(2-101)ProteinP63165 (Uniprot-TrEMBL)
SUMO1-C173-UBA2 ProteinQ9UBT2 (Uniprot-TrEMBL)
SUMO1:C93-UBE2IProteinR-HSA-2993783 (Reactome)
SUMO1:UBA2:SAE1ComplexR-HSA-2993793 (Reactome)
SUMO1ProteinP63165 (Uniprot-TrEMBL)
SUMO2(1-95)ProteinP61956 (Uniprot-TrEMBL)
SUMO2-C173-UBA2 ProteinQ9UBT2 (Uniprot-TrEMBL)
SUMO2:UBA2:SAE1ComplexR-HSA-2993775 (Reactome)
SUMO2:UBE2IProteinR-HSA-2993778 (Reactome)
SUMO2ProteinP61956 (Uniprot-TrEMBL)
SUMO3(1-103)ProteinP55854 (Uniprot-TrEMBL)
SUMO3-C173-UBA2 ProteinQ9UBT2 (Uniprot-TrEMBL)
SUMO3:UBA2:SAE1ComplexR-HSA-2993762 (Reactome)
SUMO3:UBE2IProteinR-HSA-2993782 (Reactome)
SUMO3ProteinP55854 (Uniprot-TrEMBL)
UBA2 ProteinQ9UBT2 (Uniprot-TrEMBL)
UBA2-G92-SUMO3 ProteinP55854 (Uniprot-TrEMBL)
UBA2-G93-SUMO2 ProteinP61956 (Uniprot-TrEMBL)
UBA2-G97-SUMO1 ProteinP63165 (Uniprot-TrEMBL)
UBA2:SAE1ComplexR-HSA-2990843 (Reactome)
UBE2IProteinP63279 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
AMPArrowR-HSA-2990833 (Reactome)
AMPArrowR-HSA-2993781 (Reactome)
AMPArrowR-HSA-2993784 (Reactome)
ATPR-HSA-2990833 (Reactome)
ATPR-HSA-2993781 (Reactome)
ATPR-HSA-2993784 (Reactome)
PPiArrowR-HSA-2990833 (Reactome)
PPiArrowR-HSA-2993781 (Reactome)
PPiArrowR-HSA-2993784 (Reactome)
R-HSA-2990833 (Reactome) The UBA2:SAE1 complex catalyzes the formation of a thioester bond between SUMO1 and cysteine-173 of UBA2 (Desterro et al. 1999, Okuma et al. 1999, Werner et al. 2009, Olsen et al. 2010, Wang and Chen 2010). ATP reacts with the C-terminal glycine residue of SUMO1 to yield pyrophosphate and a transient intermediate, SUMO1 adenylate, which then reacts with the thiol group of the cysteine residue on UBA2.
R-HSA-2990840 (Reactome) The SUMO1 precursor has 4 extra residues at the C-terminus which can be removed endoproteolytically by either SENP1, SENP2, or SENP5 (Zheng and Au, 2005, Mikolajczyk et al. 2007). The order of processing activity is: SENP1 greater than SENP2 greater than SENP5 (Mikolajczyk et al. 2007). Both SENP1 and SENP2 shuttle between the nucleus and cytoplasmic and both are predominantly nucleoplasmic (Bailey and O'Hare 2004, Kim et al. 2005, Zhang et al. 2002, Hang and Dasso 2002, Itahana et al. 2006).
R-HSA-2990842 (Reactome) The SUMO2 precursor has 2 extra residues at the C-terminus which can be removed endoproteolytically by SENP1, SENP2, or SENP5 (Zheng and Au, 2005, Gong and Yeh 2006, Mikolajczyk et al. 2007). The order of processing activity is: SENP1 greater than SENP2 greater than SENP5 (Mikolajczyk et al. 2007). SENP2 and SENP5 have highest activity on SUMO2, however the processing activity of SENP1 is higher overall (Mikolajczyk et al. 2007). SENP1 and SENP2 shuttle between the nucleus and cytosol and are predominantly nuclear (Bailey and O'Hare 2004, Kim et al. 2005, Zhang et al. 2002, Hang and Dasso 2002, Itahana et al. 2006). SENP5 is located in the nucleolus (Di Bacco et al. 2006, Gong and Yeh 2006).
R-HSA-2993763 (Reactome) The SUMO3 precursor has 11 extra residues at the C-terminus which can be removed endoproteolytically by SENP1, SENP2, or SENP5 (Zheng and Au, 2005, Gong and Yeh 2006, Mikolajczyk et al. 2007). The order of processing activity is: SENP1 greater than SENP2 greater than SENP5 (Mikolajczyk et al. 2007). Overall, processing of SUMO3 is the lowest of any SUMO (Mikolajczyk et al. 2007). SENP1 and SENP2 shuttle between the nucleus and cytosol and are predominantly nuclear (Bailey and O'Hare 2004, Kim et al. 2005, Zhang et al. 2002, Hang and Dasso 2002, Itahana et al. 2006). SENP5 is located in the nucleolus (Di Bacco et al. 2006, Gong and Yeh 2006).
R-HSA-2993769 (Reactome) SUMO3 is transferred from cysteine-173 of UBA2 to cysteine-93 of UBC9 (UBE2I) in a transthiolation reaction (Tatham et al. 2001, Werner et al. 2009).
R-HSA-2993780 (Reactome) SUMO1 is transferred from cysteine-173 of UBA2 to cysteine-93 of UBC9 (UBE2I) in a transthiolation reaction (Desterro et al. 1999, Okuma et al. 1999, Tatham et al. 2003, Lois and Lima 2005, Wang et al. 2007, Werner et al. 2009). The UbL domain of E1 recruits E2 into proximity for the transfer of SUMO (Lois and Lima 2005, Wang et al. 2009),
R-HSA-2993781 (Reactome) The UBA2:SAE1 complex catalyzes the formation of a thioester bond between SUMO3 and cysteine-173 of UBA2 (Tatham et al. 2001, Werner et al. 2009). ATP reacts with the C-terminal glycine residue of SUMO3 to yield pyrophosphate and a transient intermediate, SUMO3 adenylate, which then reacts with the thiol group of the cysteine residue on UBA2.
R-HSA-2993784 (Reactome) The UBA2:SAE1 complex catalyzes the formation of a thioester bond between SUMO2 and cysteine-173 of UBA2 (Tatham et al. 2001, Werner et al. 2009). ATP reacts with the C-terminal glycine residue of SUMO2 to yield pyrophosphate and a transient intermediate, SUMO2 adenylate, which then reacts with the thiol group of the cysteine residue on UBA2.
R-HSA-2993790 (Reactome) SUMO2 is transferred from cysteine-173 of UBA2 to cysteine-93 of UBC9 (UBE2I) in a transthiolation reaction (Tatham et al. 2001, Werner et al. 2009).
SENP1,2,5mim-catalysisR-HSA-2990840 (Reactome)
SENP1,2,5mim-catalysisR-HSA-2990842 (Reactome)
SENP1,2,5mim-catalysisR-HSA-2993763 (Reactome)
SUMO1(2-101)R-HSA-2990840 (Reactome)
SUMO1:C93-UBE2IArrowR-HSA-2993780 (Reactome)
SUMO1:UBA2:SAE1ArrowR-HSA-2990833 (Reactome)
SUMO1:UBA2:SAE1R-HSA-2993780 (Reactome)
SUMO1ArrowR-HSA-2990840 (Reactome)
SUMO1R-HSA-2990833 (Reactome)
SUMO2(1-95)R-HSA-2990842 (Reactome)
SUMO2:UBA2:SAE1ArrowR-HSA-2993784 (Reactome)
SUMO2:UBA2:SAE1R-HSA-2993790 (Reactome)
SUMO2:UBE2IArrowR-HSA-2993790 (Reactome)
SUMO2ArrowR-HSA-2990842 (Reactome)
SUMO2R-HSA-2993784 (Reactome)
SUMO3(1-103)R-HSA-2993763 (Reactome)
SUMO3:UBA2:SAE1ArrowR-HSA-2993781 (Reactome)
SUMO3:UBA2:SAE1R-HSA-2993769 (Reactome)
SUMO3:UBE2IArrowR-HSA-2993769 (Reactome)
SUMO3ArrowR-HSA-2993763 (Reactome)
SUMO3R-HSA-2993781 (Reactome)
UBA2:SAE1ArrowR-HSA-2993769 (Reactome)
UBA2:SAE1ArrowR-HSA-2993780 (Reactome)
UBA2:SAE1ArrowR-HSA-2993790 (Reactome)
UBA2:SAE1R-HSA-2990833 (Reactome)
UBA2:SAE1R-HSA-2993781 (Reactome)
UBA2:SAE1R-HSA-2993784 (Reactome)
UBA2:SAE1mim-catalysisR-HSA-2990833 (Reactome)
UBA2:SAE1mim-catalysisR-HSA-2993769 (Reactome)
UBA2:SAE1mim-catalysisR-HSA-2993780 (Reactome)
UBA2:SAE1mim-catalysisR-HSA-2993781 (Reactome)
UBA2:SAE1mim-catalysisR-HSA-2993784 (Reactome)
UBA2:SAE1mim-catalysisR-HSA-2993790 (Reactome)
UBE2IR-HSA-2993769 (Reactome)
UBE2IR-HSA-2993780 (Reactome)
UBE2IR-HSA-2993790 (Reactome)
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