SUMO: regulating the regulator
© Bossis and Melchior; licensee BioMed Central Ltd. 2006
Received: 14 June 2006
Accepted: 29 June 2006
Published: 29 June 2006
Post-translational modifiers of the SUMO (S mall U biquitin-related M odifier) family have emerged as key regulators of protein function and fate. While the past few years have seen an enormous increase in knowledge on SUMO enzymes, substrates, and consequences of modification, regulation of SUMO conjugation is far from being understood. This brief review will provide an overview on recent advances concerning (i) the interplay between sumoylation and other post-translational modifications at the level of individual targets and (ii) global regulation of SUMO conjugation and deconjugation.
The many roles of sumoylation
Sumoylation, which consists in the covalent and reversible conjugation of Small Ubiquitin-related Modifiers (SUMO-1, 2 and 3 in mammals) to target proteins, is an essential cellular process from yeasts to mammals. In S. cerevisiae, disruption of the SUMO pathway leads to a G2/M cell cycle arrest ; In mouse, it leads to embryonic death at early stages .
The number of known SUMO targets is growing exponentially, and it seems likely that this modification is as common as phosphorylation to regulate biological processes . Most SUMO targets were initially found in the nucleus, but it is now clear that sumoylation also regulates cytoplasmic-, and even plasma membrane associated proteins. Modification has been linked to pathways as diverse as intracellular trafficking, cell cycle, DNA repair and replication, RNA metabolism and cell signalling (for detailed description of sumoylation functions see ). At a molecular level, sumoylation alters protein functions by masking and/or adding interaction surfaces, or by inducing conformational changes that result in altered interactions (for detailed examples see ). As a consequence, a wide variety of downstream consequences have been observed, including changes in localisation, enzymatic activity, or stability.
Among the many known targets of sumoylation, a large number are regulators of gene expression, in particular transcription factors, co-activators or repressors. Here, the emerging picture is that sumoylation essentially results in down-regulation of gene expression. Albeit the molecular mechanisms underlying this repression by SUMO are still ill defined, they seem to involve SUMO-dependent recruitment of transcriptional repressors such as HDACs directly to promoters .
The SUMO conjugation and deconjugation pathway
SUMO-target conjugates are susceptible to cleavage by specific cysteine proteases (SUMO isopeptidases) . In yeast, two isopeptidases, Ulp1 and Ulp2, are responsible for SUMO deconjugation. Homologs of the Ulp family were identified by sequence homology and referred to as SENP proteins (1 to 8). SUMO isopeptidase activity was confirmed for SENP-1 , SENP-2 [9–11], SENP-3 [12, 13], SENP5  and SENP6 . SENP-8, however, turned out to be a NEDD8 specific isopeptidase [15–17]. Whether other types of SUMO isopeptidases exist is still not clear. All SENPs share a conserved catalytic domain but have distinct N-terminal extensions, which might be responsible for their different intracellular localisations .
The interplay between modifying enzymes and isopeptidases is responsible, at least in part, for the late discovery of SUMO: with rare exceptions such as RanGAP1, the first protein for which sumoylation was shown, most SUMO targets are modified at very low steady state levels in vivo. Moreover, upon cell lysis most sumoylated proteins are highly susceptible to demodification by isopeptidases. Dynamic sumoylation/desumoylation cycles may also be responsible for a frequently observed conundrum: while only a small fraction of a given target is sumoylated at steady state, their corresponding SUMOylation-deficient mutants can have striking effects .
Regulation of sumoylation at the substrate level
While selected SUMO targets are modified constitutively, many proteins are sumoylated in a temporally or spatially regulated fashion. Examples for target specific regulation are mitotic modification of yeast septins  and topoisomerase II , PML demodification  in mitosis, S. c. PCNA sumoylation in S-phase [21, 22], stress induced sumoylation of heat shock factor I , or circadian cycle dependant sumoylation of BMAL1 . While only fragmented knowledge concerning this regulation is available, it is already clear that there are several distinct mechanisms to enhance or inhibit sumoylation of individual target proteins.
In other cases, phosphorylation can enhance sumoylation. This was first demonstrated for the Heat Shock Factor HSF1. Its phosphorylation on Ser 303, induced after heat shock, is required for efficient sumoylation on the nearby Lys 298 . A S303E mutant is more efficiently sumoylated than wt even in vitro, suggesting that the underlying mechanism is enhanced recruitment of the E2 conjugating enzyme Ubc9 E3 (ligases were absent in the assay). Whether this involves a conformational change or whether the acidic residue contributes directly to Ubc9 association awaits further analysis. Importantly, these findings could be generalized: The sequence motif, ΨKxExxSP, which is now referred to as P hosphorylation D ependent S umoylation M otif (PDSM) , is present in various proteins, predominantly transcriptional regulators. For several of these (HSF4, GATA-1, MEF2, SNIP-1 and ERRγ) the authors demonstrated that serine phosphorylation in the PDSM indeed enhances their sumoylation . Phosphorylation dependent sumoylation of MEF2 family members was also reported by other groups [31, 32].
Regulated MEF2 sumoylation seems to actually involve an added level of complexity: Zhao and coworkers  had already observed that MEF2D can be sumoylated or acetylated on the same lysine residue. A report by Shalizi et al.,  now brings together phosphorylation, acetylation and sumoylation of MEF2A: Calcineurin dependent dephosphorylation of Ser 408 in MEF2A, which is located in the PDSM, was shown to promote a switch from sumoylation to acetylation at lysine 403. Consequently, sumoylation of MEF2 is inhibited not only by the lack of the phosphate in the PDSM, but also by direct competition of acetylation and sumoylation on the same lysine residue.
The concept that sumoylation and acetylation are two competing modifications for the same lysine residue in some SUMO targets is actually not new – it has been first noted for the transcription factor Sp3 , and was also shown for the transcriptional co-activator p300, whose deacetylation by SIRT1 is required for its efficient sumoylation . Whether sumoylation serves to inhibit acetylation, whether acetylation serves to prevent sumoylation, or whether the sumoylated, acetylated and non-modified species serve independent functions is one of many interesting questions that arise from these studies. One particularly interesting question is whether lysine acetylation frequently overlaps with SUMO acceptor sites.
Lysine residues are obviously not only targets for sumoylation and acetylation, but can, e.g., also be ubiquitinylated. This brings us to another type of competing modifications – ubiquitinylation and sumoylation (Figure 2). The first example is Iκ-Bα that can be poly-ubiquitinylated or mono-sumoylated on lysine 21 . While poly-ubiquitinylation and subsequent degradation by the proteasome requires signal-induced phosphorylation of Iκ-Bα, sumoylation takes place in the absense of phosphorylation. It has been suggested that SUMO serves to protect Iκ-Bα from degradation, however only a very small fraction of Iκ-Bα is sumoylated at steady state. More recently, it has been shown that NEMO, the Iκ-B kinase (IKK) regulator, is also subject to both modifications on the same lysine . Here, sumoylation/desumoylation and ubiquitinylation may be independent, but consecutive, events in the activation pathway . Finally, S.c. and Xenopus laevis PCNA were shown to be mono-ubiquitinylated, poly-ubiquitinylated (K63 chains) or sumoylated on lysine 164. Different modifications are induced by different cues (e.g., cell cycle position or DNA damage), and have distinct as well as cooperative functions in DNA repair and replication (reviewed in ). In conclusion, quantitative and stable modification of a given target with SUMO or ubiquitin would obviously prevent modification with the other moiety, and either modifier could hence serve as an antagonist of the other. However, from the currently known data it seems more likely that both types of modifications are regulated independent of each other and serve different roles (reviewed in ).
The mechanisms discussed above all involve posttranslational modifications of the target protein. Similar mechanisms can obviously be envisioned at the level of target specific E3 ligases or isopeptidases. Modification of these enzymes may well alter their ability to interact with specific target proteins. Finally, many enzymes in the SUMO pathway have restricted intracellular localisations (reviewed in ). Hence sumoylation/desumoylation of specific targets requires targeting to those sites. This has, e.g., been shown for SP100, whose sumoylation requires nuclear targeting . Consequently, any event that changes target or enzyme position within the cell may influence the extent of sumoylation for a specific target. An intriguing example is the relocalisation of the S. cerevisiae E3 ligase Siz1 from the nucleus to the bud neck in mitosis, which results in septin sumoylation .
Regulation of the SUMO conjugating and deconjugating enzymes
The SUMO conjugation/deconjugation pathway is also globally regulated by stresses. Various stresses, including heat shock, osmotic and high oxidative stress (H2O2) enhance global sumoylation both in mammals , plants and yeasts . In mammals, the increase of conjugates was largely observed for SUMO-2/3 but not for SUMO-1. The apparent difference in stress response between SUMO-1 and SUMO-2/3 may point to some interesting difference in regulation, but could also have a rather trivial explanation: there is a large pool of free SUMO-2 and -3 but limited SUMO-1 under normal conditions . A significant increase of SUMO-2/3 conjugation has also been observed in HEK293 cells exposed to the lipid oxidation-derived electrophile 4-hydroxynonenal, which is an ubiquitous product of lipid oxidation associated with oxidative stress .
In the case of oxidative stress in mammalian cells, the situation is more complex than it first appeared. Indeed, increased SUMO conjugation was observed only in conditions of extreme oxidative stress (100 mM H2O2), which does not occur under physiological or even pathophysiological conditions in vivo. At more relevant concentrations (1 mM and below), H2O2 has opposite effects on SUMO conjugation, leading to almost complete loss of SUMO-1, -2 and -3 conjugates. Mechanistically, this is due to direct inhibition of SUMO conjugation by induction of a reversible disulfide bridge between the catalytic cysteines of the E1 subunit Uba2 and the E2 Ubc9. Under those conditions, SUMO isopeptidases, which also have a cysteine in their active site, are almost not affected . As a consequence, this shifts the equilibrium in the sumoylation-desumoylation cycle towards unconjugated species (increased sumoylation at the unphysiological dose of 100 mM H2O2 can perhaps be explained by simultaneous inhibition of modifying and demodifying isopeptidases enzymes). What is the benefit for the cell to block sumoylation in case of oxidative stress? Again, this might help to activate transcription of genes involved in the return to normal redox conditions. Supporting this explanation, AP-1 transcription factors c-Fos and c-Jun are desumoylated within a few minutes after H2O2 addition to the cells. Considering that (i) sumoylation represses their activity [25, 26] and (ii) they play a key role in the transcriptional activation of numerous anti-oxidant proteins , their rapid desumoylation might play a key role in the early response to oxidative stress.
The sensitivity of SUMO pathway enzymes towards reversible inactivation by oxidation raises the question of whether this mechanism is also important for physiological processes that involve redox signaling. Unlike "oxidative stress" which is characterized by a macroscopic shift in cellular redox potential, redox signaling involves reversible, locally and chemically defined, oxidations of key enzymes in signaling pathways [54, 55]. This involves, e.g., peptide growth factor induced activation of membrane associated NADPH oxidases that produce H2O2. NADPH-Oxidase complexes have been found in most cell types. Transient accumulation of hydrogen peroxide is known to participate in receptor signaling by, e.g., reversibly oxidizing the essential cysteine residues of protein tyrosine phosphatases and the lipid phosphatase PTEN .
Highest levels of endogenous H2O2 production are known to occur in phagocytic cells. Their activation by endotoxins (such as LPS) or inflammatory mediators (such as TNF, Interferon or Phorbol esters) is responsible for the so-called respiratory burst, which consists in the production of ROS by a specific NADPH oxidase complex called Phox . While it was long thought that this ROS production was only aimed at killing the engulfed pathogen, it is now known that these ROS also play a key role as second messengers in AP-1 and NF-κB signaling pathways . At least in this system, or more precisely in a macrophage cell line activated by PMA and zymosan, endogenously produced H2O2 is sufficient to reversibly inactivate a significant fraction of cytoplasmic SUMO E1 and E2 enzymes. While the global pattern of SUMO conjugates remains unchanged, some demodification of unknown proteins has been observed . One attractive hypothesis is that signal induced desumoylation of specific proteins in the immediate vicinity of NADPH oxidases, both in macrophages and other cell types, may contribute to activation of signal transduction and subsequent cellular responses.
Considering the enormous number of sumoylated proteins that are modified in temporally and spatially controlled manner, the number of known enzymes is surprisingly limited. Nevertheless, in vitro, these enzymes are sufficient to modify many proteins. To account for the high specificity observed in vivo, we therefore have to assume the existence of many regulatory mechanisms. As outlined in this review, we are now beginning to understand how sumoylation can be regulated -mechanisms such as phosphorylation of selected targets and enzymes, antagonistic modifications and local inactivation by oxidation appear to contribute at the level of individual targets and in some scenarios globally. Different aspects of these and other regulatory mechanisms will undoubtedly be the focus of many exciting contributions over the next few years.
- Seufert W, Futcher B, Jentsch S: Role of a ubiquitin-conjugating enzyme in degradation of S- and M-phase cyclins. Nature 1995, 373: 78–81. 10.1038/373078a0PubMedView ArticleGoogle Scholar
- Nacerddine K, Lehembre F, Bhaumik M, Artus J, Cohen-Tannoudji M, Babinet C, Pandolfi PP, Dejean A: The SUMO pathway is essential for nuclear integrity and chromosome segregation in mice. Dev Cell 2005, 9: 769–779. 10.1016/j.devcel.2005.10.007PubMedView ArticleGoogle Scholar
- Marx J: Cell biology. SUMO wrestles its way to prominence in the cell. Science 2005, 307: 836–839. 10.1126/science.307.5711.836PubMedView ArticleGoogle Scholar
- Hay RT: SUMO: a history of modification. Mol Cell 2005, 18: 1–12. 10.1016/j.molcel.2005.03.012PubMedView ArticleGoogle Scholar
- Johnson ES: Protein modification by SUMO. Annu Rev Biochem 2004, 73: 355–382. 10.1146/annurev.biochem.73.011303.074118PubMedView ArticleGoogle Scholar
- Gill G: Something about SUMO inhibits transcription. Curr Opin Genet Dev 2005, 15: 536–541. 10.1016/j.gde.2005.07.004PubMedView ArticleGoogle Scholar
- Melchior F, Schergaut M, Pichler A: SUMO: ligases, isopeptidases and nuclear pores. Trends Biochem Sci 2003, 28: 612–618. 10.1016/j.tibs.2003.09.002PubMedView ArticleGoogle Scholar
- Bailey D, O'Hare P: Characterization of the localization and proteolytic activity of the SUMO-specific protease, SENP1. J Biol Chem 2004, 279: 692–703. 10.1074/jbc.M306195200PubMedView ArticleGoogle Scholar
- Best JL, Ganiatsas S, Agarwal S, Changou A, Salomoni P, Shirihai O, Meluh PB, Pandolfi PP, Zon LI: SUMO-1 protease-1 regulates gene transcription through PML. Mol Cell 2002, 10: 843–855. 10.1016/S1097-2765(02)00699-8PubMedView ArticleGoogle Scholar
- Kadoya T, Yamamoto H, Suzuki T, Yukita A, Fukui A, Michiue T, Asahara T, Tanaka K, Asashima M, Kikuchi A: Desumoylation activity of Axam, a novel Axin-binding protein, is involved in downregulation of beta-catenin. Mol Cell Biol 2002, 22: 3803–3819. 10.1128/MCB.22.11.3803-3819.2002PubMed CentralPubMedView ArticleGoogle Scholar
- Nishida T, Kaneko F, Kitagawa M, Yasuda H: 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: 39060–39066. 10.1074/jbc.M103955200PubMedView ArticleGoogle Scholar
- 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: 6423–6427. 10.1046/j.1432-1327.2000.01729.xPubMedView ArticleGoogle Scholar
- 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.Google Scholar
- Kim KI, Baek SH, Jeon YJ, Nishimori S, Suzuki T, Uchida S, Shimbara N, Saitoh H, Tanaka K, Chung CH: A new SUMO-1-specific protease, SUSP1, that is highly expressed in reproductive organs. J Biol Chem 2000, 275: 14102–14106. 10.1074/jbc.275.19.14102PubMedView ArticleGoogle Scholar
- Gan-Erdene T, Nagamalleswari K, Yin L, Wu K, Pan ZQ, Wilkinson KD: Identification and characterization of DEN1, a deneddylase of the ULP family. J Biol Chem 2003, 278: 28892–28900. 10.1074/jbc.M302890200PubMedView ArticleGoogle Scholar
- Mendoza HM, Shen LN, Botting C, Lewis A, Chen J, Ink B, Hay RT: NEDP1, a highly conserved cysteine protease that deNEDDylates Cullins. J Biol Chem 2003, 278: 25637–25643. 10.1074/jbc.M212948200PubMedView ArticleGoogle Scholar
- Wu K, Yamoah K, Dolios G, Gan-Erdene T, Tan P, Chen A, Lee CG, Wei N, Wilkinson KD, Wang R, Pan ZQ: DEN1 is a dual function protease capable of processing the C terminus of Nedd8 and deconjugating hyper-neddylated CUL1. J Biol Chem 2003, 278: 28882–28891. 10.1074/jbc.M302888200PubMedView ArticleGoogle Scholar
- Johnson ES, Blobel G: Cell cycle-regulated attachment of the ubiquitin-related protein SUMO to the yeast septins. J Cell Biol 1999, 147: 981–994. 10.1083/jcb.147.5.981PubMed CentralPubMedView ArticleGoogle Scholar
- Azuma Y, Arnaoutov A, Dasso M: SUMO-2/3 regulates topoisomerase II in mitosis. J Cell Biol 2003, 163: 477–487. 10.1083/jcb.200304088PubMed CentralPubMedView ArticleGoogle Scholar
- Everett RD, Lomonte P, Sternsdorf T, van Driel R, Orr A: Cell cycle regulation of PML modification and ND10 composition. J Cell Sci 1999, 112 ( Pt 24): 4581–4588.Google Scholar
- Papouli E, Chen S, Davies AA, Huttner D, Krejci L, Sung P, Ulrich HD: Crosstalk between SUMO and ubiquitin on PCNA is mediated by recruitment of the helicase Srs2p. Mol Cell 2005, 19: 123–133. 10.1016/j.molcel.2005.06.001PubMedView ArticleGoogle Scholar
- Pfander B, Moldovan GL, Sacher M, Hoege C, Jentsch S: SUMO-modified PCNA recruits Srs2 to prevent recombination during S phase. Nature 2005, 436: 428–433.PubMedGoogle Scholar
- Hong Y, Rogers R, Matunis MJ, Mayhew CN, Goodson ML, Park-Sarge OK, Sarge KD: Regulation of heat shock transcription factor 1 by stress-induced SUMO-1 modification. J Biol Chem 2001, 276: 40263–40267.PubMedView ArticleGoogle Scholar
- Cardone L, Hirayama J, Giordano F, Tamaru T, Palvimo JJ, Sassone-Corsi P: Circadian clock control by SUMOylation of BMAL1. Science 2005, 309: 1390–1394. 10.1126/science.1110689PubMedView ArticleGoogle Scholar
- Muller S, Berger M, Lehembre F, Seeler JS, Haupt Y, Dejean A: c-Jun and p53 activity is modulated by SUMO-1 modification. J Biol Chem 2000, 275: 13321–13329. 10.1074/jbc.275.18.13321PubMedView ArticleGoogle Scholar
- Bossis G, Malnou CE, Farras R, Andermarcher E, Hipskind R, Rodriguez M, Schmidt D, Muller S, Jariel-Encontre I, Piechaczyk M: Down-regulation of c-Fos/c-Jun AP-1 dimer activity by sumoylation. Mol Cell Biol 2005, 25: 6964–6979. 10.1128/MCB.25.16.6964-6979.2005PubMed CentralPubMedView ArticleGoogle Scholar
- Lin JY, Ohshima T, Shimotohno K: Association of Ubc9, an E2 ligase for SUMO conjugation, with p53 is regulated by phosphorylation of p53. FEBS Lett 2004, 573: 15–18. 10.1016/j.febslet.2004.07.059PubMedView ArticleGoogle Scholar
- Yang SH, Jaffray E, Hay RT, Sharrocks AD: Dynamic interplay of the SUMO and ERK pathways in regulating Elk-1 transcriptional activity. Mol Cell 2003, 12: 63–74. 10.1016/S1097-2765(03)00265-XPubMedView ArticleGoogle Scholar
- Hietakangas V, Ahlskog JK, Jakobsson AM, Hellesuo M, Sahlberg NM, Holmberg CI, Mikhailov A, Palvimo JJ, Pirkkala L, Sistonen L: Phosphorylation of serine 303 is a prerequisite for the stress-inducible SUMO modification of heat shock factor 1. Mol Cell Biol 2003, 23: 2953–2968. 10.1128/MCB.23.8.2953-2968.2003PubMed CentralPubMedView ArticleGoogle Scholar
- Hietakangas V, Anckar J, Blomster HA, Fujimoto M, Palvimo JJ, Nakai A, Sistonen L: PDSM, a motif for phosphorylation-dependent SUMO modification. Proc Natl Acad Sci U S A 2006, 103: 45–50. 10.1073/pnas.0503698102PubMed CentralPubMedView ArticleGoogle Scholar
- Kang J, Gocke CB, Yu H: Phosphorylation-facilitated sumoylation of MEF2C negatively regulates its transcriptional activity. BMC Biochem 2006, 7: 5. 10.1186/1471-2091-7-5PubMed CentralPubMedView ArticleGoogle Scholar
- Gregoire S, Tremblay AM, Xiao L, Yang Q, Ma K, Nie J, Mao Z, Wu Z, Giguere V, Yang XJ: Control of MEF2 transcriptional activity by coordinated phosphorylation and sumoylation. J Biol Chem 2006, 281: 4423–4433. 10.1074/jbc.M509471200PubMedView ArticleGoogle Scholar
- Zhao X, Sternsdorf T, Bolger TA, Evans RM, Yao TP: Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications. Mol Cell Biol 2005, 25: 8456–8464. 10.1128/MCB.25.19.8456-8464.2005PubMed CentralPubMedView ArticleGoogle Scholar
- Shalizi A, Gaudilliere B, Yuan Z, Stegmuller J, Shirogane T, Ge Q, Tan Y, Schulman B, Harper JW, Bonni A: A calcium-regulated MEF2 sumoylation switch controls postsynaptic differentiation. Science 2006, 311: 1012–1017. 10.1126/science.1122513PubMedView ArticleGoogle Scholar
- Sapetschnig A, Rischitor G, Braun H, Doll A, Schergaut M, Melchior F, Suske G: Transcription factor Sp3 is silenced through SUMO modification by PIAS1. Embo J 2002, 21: 5206–5215. 10.1093/emboj/cdf510PubMed CentralPubMedView ArticleGoogle Scholar
- Bouras T, Fu M, Sauve AA, Wang F, Quong AA, Perkins ND, Hay RT, Gu W, Pestell RG: SIRT1 deacetylation and repression of p300 involves lysine residues 1020/1024 within the cell cycle regulatory domain 1. J Biol Chem 2005, 280: 10264–10276. 10.1074/jbc.M408748200PubMedView ArticleGoogle Scholar
- Desterro JM, Rodriguez MS, Hay RT: SUMO-1 modification of IkappaBalpha inhibits NF-kappaB activation. Mol Cell 1998, 2: 233–239. 10.1016/S1097-2765(00)80133-1PubMedView ArticleGoogle Scholar
- Huang TT, Wuerzberger-Davis SM, Wu ZH, Miyamoto S: Sequential modification of NEMO/IKKgamma by SUMO-1 and ubiquitin mediates NF-kappaB activation by genotoxic stress. Cell 2003, 115: 565–576. 10.1016/S0092-8674(03)00895-XPubMedView ArticleGoogle Scholar
- Hay RT: Modifying NEMO. Nat Cell Biol 2004, 6: 89–91. 10.1038/ncb0204-89PubMedView ArticleGoogle Scholar
- Watts FZ: Sumoylation of PCNA: Wrestling with recombination at stalled replication forks. DNA Repair (Amst) 2006, 5: 399–403. 10.1016/j.dnarep.2005.11.002View ArticleGoogle Scholar
- Ulrich HD: Mutual interactions between the SUMO and ubiquitin systems: a plea of no contest. Trends Cell Biol 2005, 15: 525–532. 10.1016/j.tcb.2005.08.002PubMedView ArticleGoogle Scholar
- 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 1999, 274: 12555–12566. 10.1074/jbc.274.18.12555PubMedView ArticleGoogle Scholar
- Johnson ES, Gupta AA: An E3-like factor that promotes SUMO conjugation to the yeast septins. Cell 2001, 106: 735–744. 10.1016/S0092-8674(01)00491-3PubMedView ArticleGoogle Scholar
- Muller S, Dejean A: Viral immediate-early proteins abrogate the modification by SUMO-1 of PML and Sp100 proteins, correlating with nuclear body disruption. J Virol 1999, 73: 5137–5143.PubMed CentralPubMedGoogle Scholar
- Ledl A, Schmidt D, Muller S: Viral oncoproteins E1A and E7 and cellular LxCxE proteins repress SUMO modification of the retinoblastoma tumor suppressor. Oncogene 2005, 24: 3810–3818. 10.1038/sj.onc.1208539PubMedView ArticleGoogle Scholar
- Parkinson J, Everett RD: Alphaherpesvirus proteins related to herpes simplex virus type 1 ICP0 affect cellular structures and proteins. J Virol 2000, 74: 10006–10017. 10.1128/JVI.74.21.10006-10017.2000PubMed CentralPubMedView ArticleGoogle Scholar
- Boggio R, Colombo R, Hay RT, Draetta GF, Chiocca S: A mechanism for inhibiting the SUMO pathway. Mol Cell 2004, 16: 549–561. 10.1016/j.molcel.2004.11.007PubMedView ArticleGoogle Scholar
- Saitoh H, Hinchey J: Functional heterogeneity of small ubiquitin-related protein modifiers SUMO-1 versus SUMO-2/3. J Biol Chem 2000, 275: 6252–6258. 10.1074/jbc.275.9.6252PubMedView ArticleGoogle Scholar
- Kurepa J, Walker JM, Smalle J, Gosink MM, Davis SJ, Durham TL, Sung DY, Vierstra RD: The small ubiquitin-like modifier (SUMO) protein modification system in Arabidopsis. Accumulation of SUMO1 and -2 conjugates is increased by stress. J Biol Chem 2003, 278: 6862–6872. 10.1074/jbc.M209694200PubMedView ArticleGoogle Scholar
- Zhou W, Ryan JJ, Zhou H: Global analyses of sumoylated proteins in Saccharomyces cerevisiae. Induction of protein sumoylation by cellular stresses. J Biol Chem 2004, 279: 32262–32268. 10.1074/jbc.M404173200PubMed CentralPubMedView ArticleGoogle Scholar
- Manza LL, Codreanu SG, Stamer SL, Smith DL, Wells KS, Roberts RL, Liebler DC: Global shifts in protein sumoylation in response to electrophile and oxidative stress. Chem Res Toxicol 2004, 17: 1706–1715. 10.1021/tx049767lPubMedView ArticleGoogle Scholar
- Bossis G, Melchior F: Regulation of SUMOylation by reversible oxidation of SUMO conjugating enzymes. Mol Cell 2006, 21: 349–357. 10.1016/j.molcel.2005.12.019PubMedView ArticleGoogle Scholar
- Gius D, Botero A, Shah S, Curry HA: Intracellular oxidation/reduction status in the regulation of transcription factors NF-kappaB and AP-1. Toxicol Lett 1999, 106: 93–106. 10.1016/S0378-4274(99)00024-7PubMedView ArticleGoogle Scholar
- Lambeth JD: NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 2004, 4: 181–189. 10.1038/nri1312PubMedView ArticleGoogle Scholar
- Rhee SG, Kang SW, Jeong W, Chang TS, Yang KS, Woo HA: Intracellular messenger function of hydrogen peroxide and its regulation by peroxiredoxins. Curr Opin Cell Biol 2005, 17: 183–189. 10.1016/j.ceb.2005.02.004PubMedView ArticleGoogle Scholar
- Forman HJ, Torres M: Reactive oxygen species and cell signaling: respiratory burst in macrophage signaling. Am J Respir Crit Care Med 2002, 166: S4–8. 10.1164/rccm.2206007PubMedView ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.