Emerging Role of SUMO in Pancreatic β-Cells

Abstract

Post-translational attachment of small ubiquitin-like modifier (SUMO), defined as SUMOylation, can affect the localization, interactions, stability and/or activity of substrate proteins, and thus can participate in a large variety of cellular processes. Most SUMO substrates are involved in transcriptional regulation. Hence, SUMOylation can either activate or, more commonly, repress gene transcription. The modulation of gene expression by SUMO through diverse mechanisms and specifically the recent findings concerning SUMOylation in pancreatic β-cells are reviewed.

Key words

insulin - diabetes - ICA512 - PDX-1 - Maf-A - STAT - PIAS

References

• 1 Matunis MJ, 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. 1996;  135 1457-1470
• 2 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. 1997;  88 97-107
• 3 Melchior F. SUMO-nonclassical ubiquitin.  Annu Rev Cell Dev Biol. 2000;  16 591-626
• 4 Muller S, Hoege C, Pyrowolakis G, Jentsch S. SUMO, ubiquitin's mysterious cousin.  Nat Rev Mol Cell Biol. 2001;  2 202-210
• 5 Swanson KA, Kang RS, Stamenova SD, Hicke L, Radhakrishnan I. Solution structure of Vps27 UIM-ubiquitin complex important for endosomal sorting and receptor downregulation.  Embo J. 2003;  22 4597-4606
• 6 Panse VG, Hardeland U, Werner T, Kuster B, Hurt E. A proteome-wide approach identifies sumoylated substrate proteins in yeast.  J Biol Chem. 2004;  279 41346-41351
• 7 Wohlschlegel JA, Johnson ES, Reed SI, Yates 3rd JR. Improved identification of SUMO attachment sites using C-terminal SUMO mutants and tailored protease digestion strategies.  J Proteome Res. 2006;  5 761-770
• 8 Denison C, Rudner AD, Gerber SA. et al . A proteomic strategy for gaining insights into protein sumoylation in yeast.  Mol Cell Proteomics. 2005;  4 246-254
• 9 Hannich JT, Lewis A, Kroetz MB. et al . Defining the SUMO-modified proteome by multiple approaches in Saccharomyces cerevisiae.  J Biol Chem. 2005;  280 4102-4110
• 10 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
• 11 Tatham MH, Kim S, Yu B. et al . Role of an N-terminal site of Ubc9 in SUMO-1, -2, and -3 binding and conjugation.  Biochemistry. 2003;  42 9959-9969
• 12 Johnson ES, Gupta AA. An E3-like factor that promotes SUMO conjugation to the yeast septins.  Cell. 2001;  106 735-744
• 13 Tatham MH, Jaffray E, Vaughan OA. et al . Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9.  J Biol Chem. 2001;  276 35368-35374
• 14 Pichler A, Gast A, Seeler JS, Dejean A, Melchior F. The nucleoporin RanBP2 has SUMO1 E3 ligase activity.  Cell. 2002;  108 109-120
• 15 Bylebyl GR, Belichenko I, Johnson ES. The SUMO isopeptidase Ulp2 prevents accumulation of SUMO chains in yeast.  J Biol Chem. 2003;  278 44113-44120
• 16 Pedrioli PG, Raught B, Zhang XD. et al . Automated identification of SUMOylation sites using mass spectrometry and SUMmOn pattern recognition software.  Nat Methods. 2006;  3 533-539
• 17 Yang M, Hsu CT, Ting CY, Liu LF, Hwang J. Assembly of a polymeric chain of SUMO1 on human topoisomerase I in vitro.  J Biol Chem. 2006;  281 8264-8274
• 18 Owerbach D, Pina L, Gabbay KH. A 212-kb region on chromosome 6q25 containing the TAB2 gene is associated with susceptibility to type 1 diabetes.  Diabetes. 2004;  53 1890-1893
• 19 Bohren KM, Nadkarni V, Song JH, Gabbay KH, Owerbach D. A M55 V polymorphism in a novel SUMO gene (SUMO-4) differentially activates heat shock transcription factors and is associated with susceptibility to type I diabetes mellitus.  J Biol Chem. 2004;  279 27233-27238
• 20 Su HL, Li SS. Molecular features of human ubiquitin-like SUMO genes and their encoded proteins.  Gene. 2002;  296 65-73
• 21 Schmidt D, Muller S. PIAS/SUMO: new partners in transcriptional regulation.  Cell Mol Life Sci. 2003;  60 2561-2574
• 22 Gong L, Yeh ET. Characterization of a family of nucleolar SUMO-specific proteases with preference for SUMO-2 or SUMO-3.  J Biol Chem. 2006;  281 15869-15877
• 23 Rodriguez MS, Dargemont C, Hay RT. SUMO-1 conjugation in vivo requires both a consensus modification motif and nuclear targeting.  J Biol Chem. 2001;  276 12654-12659
• 24 Johnson ES, Schwienhorst I, Dohmen RJ, Blobel G. The ubiquitin-like protein Smt3p is activated for conjugation to other proteins by an Aos1p/Uba2p heterodimer.  Embo J. 1997;  16 5509-5519
• 25 Desterro JM, Rodriguez MS, Kemp GD, Hay RT. Identification of the enzyme required for activation of the small ubiquitin-like protein SUMO-1.  J Biol Chem. 1999;  274 10618-10624
• 26 Gong L, Li B, Millas S, Yeh ET. Molecular cloning and characterization of human AOS1 and UBA2, components of the sentrin-activating enzyme complex.  FEBS Lett. 1999;  448 185-189
• 27 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. 1999;  254 693-698
• 28 Desterro JM, Thomson J, Hay RT. Ubch9 conjugates SUMO but not ubiquitin.  FEBS Lett. 1997;  417 297-300
• 29 Johnson ES, Blobel G. Ubc9p is the conjugating enzyme for the ubiquitin-like protein Smt3p.  J Biol Chem. 1997;  272 26799-26802
• 30 Bernier-Villamor V, Sampson DA, Matunis MJ, Lima CD. Structural basis for E2-mediated SUMO conjugation revealed by a complex between ubiquitin-conjugating enzyme Ubc9 and RanGAP1.  Cell. 2002;  108 345-356
• 31 Pickart CM. Mechanisms underlying ubiquitination.  Annu Rev Biochem. 2001;  70 503-533
• 32 Kahyo T, Nishida T, Yasuda H. Involvement of PIAS1 in the sumoylation of tumor suppressor p53.  Mol Cell. 2001;  8 713-718
• 33 Sachdev S, Bruhn L, Sieber H. et al . PIASy, a nuclear matrix-associated SUMO E3 ligase, represses LEF1 activity by sequestration into nuclear bodies.  Genes Dev. 2001;  15 3088-3103
• 34 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. 2002;  99 2872-2877
• 35 Duprez E, Saurin AJ, Desterro JM. et al . SUMO-1 modification of the acute promyelocytic leukaemia protein PML: implications for nuclear localisation.  J Cell Sci. 1999;  112 ((Pt 3)) 381-393
• 36 Rangasamy D, Woytek K, Khan SA, Wilson VG. SUMO-1 modification of bovine papillomavirus E1 protein is required for intranuclear accumulation.  J Biol Chem. 2000;  275 37999-38004
• 37 Kagey MH, Melhuish TA, Wotton D. The polycomb protein Pc2 is a SUMO E3.  Cell. 2003;  113 127-137
• 38 Verger A, Perdomo J, Crossley M. Modification with SUMO. A role in transcriptional regulation.  EMBO Rep. 2003;  4 137-142
• 39 Muller S, Ledl A, Schmidt D. SUMO: a regulator of gene expression and genome integrity.  Oncogene. 2004;  23 1998-2008
• 40 Seeler JS, Dejean A. Nuclear and unclear functions of SUMO.  Nat Rev Mol Cell Biol. 2003;  4 690-699
• 41 Girdwood DW, Tatham MH, Hay RT. SUMO and transcriptional regulation.  Semin Cell Dev Biol. 2004;  15 201-210
• 42 Yamamoto H, Ihara M, Matsuura Y, Kikuchi A. Sumoylation is involved in beta-catenin-dependent activation of Tcf-4.  Embo J. 2003;  22 2047-2059
• 43 Gomez-del Arco P, Koipally J, Georgopoulos K. Ikaros SUMOylation: switching out of repression.  Mol Cell Biol. 2005;  25 2688-2697
• 44 Poukka H, Karvonen U, Janne OA, Palvimo JJ. Covalent modification of the androgen receptor by small ubiquitin-like modifier 1 (SUMO-1).  Proc Natl Acad Sci USA. 2000;  97 14145-14150
• 45 Kim J, Cantwell CA, Johnson PF, Pfarr CM, Williams SC. Transcriptional activity of CCAAT/enhancer-binding proteins is controlled by a conserved inhibitory domain that is a target for sumoylation.  J Biol Chem. 2002;  277 38037-38044
• 46 Gill G. Post-translational modification by the small ubiquitin-related modifier SUMO has big effects on transcription factor activity.  Curr Opin Genet Dev. 2003;  13 108-113
• 47 Subramanian L, Benson MD, Iniguez-Lluhi JA. A synergy control motif within the attenuator domain of CCAAT/enhancer-binding protein alpha inhibits transcriptional synergy through its PIASy-enhanced modification by SUMO-1 or SUMO-3.  J Biol Chem. 2003;  278 9134-9141
• 48 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
• 49 Ross S, Best JL, Zon LI, Gill G. SUMO-1 modification represses Sp3 transcriptional activation and modulates its subnuclear localization.  Mol Cell. 2002;  10 831-842
• 50 Sapetschnig A, Rischitor G, Braun H. et al . Transcription factor Sp3 is silenced through SUMO modification by PIAS1.  Embo J. 2002;  21 5206-5215
• 51 Long J, Wang G, He D, Liu F. Repression of Smad4 transcriptional activity by SUMO modification.  Biochem J. 2004;  379 23-29
• 52 Eloranta JJ, Hurst HC. Transcription factor AP-2 interacts with the SUMO-conjugating enzyme UBC9 and is sumolated in vivo.  J Biol Chem. 2002;  277 30798-30804
• 53 Johnson ES. Protein modification by SUMO.  Annu Rev Biochem. 2004;  73 355-382
• 54 Desterro JM, Rodriguez MS, Hay RT. SUMO-1 modification of I kappa B alpha inhibits NF-kappaB activation.  Mol Cell. 1998;  2 233-239
• 55 Hay RT, Vuillard L, Desterro JM, Rodriguez MS. Control of NF-kappa B transcriptional activation by signal induced proteolysis of I kappa B alpha.  Philos Trans R Soc Lond B Biol Sci. 1999;  354 1601-1609
• 56 Hoege C, Pfander B, Moldovan GL, Pyrowolakis G, Jentsch S. RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO.  Nature. 2002;  419 135-141
• 57 Muller S, Matunis MJ, Dejean A. Conjugation with the ubiquitin-related modifier SUMO-1 regulates the partitioning of PML within the nucleus.  Embo J. 1998;  17 61-70
• 58 Everett RD, Lomonte P, Sternsdorf T, Driel R van, Orr A. Cell cycle regulation of PML modification and ND10 composition.  J Cell Sci. 1999;  112 ((Pt 24)) 4581-4588
• 59 Muller S, Berger M, Lehembre F. et al . c-Jun and p53 activity is modulated by SUMO-1 modification.  J Biol Chem. 2000;  275 13321-13329
• 60 Hietakangas V, Ahlskog JK, Jakobsson AM. et al . 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
• 61 Yang XJ, Gregoire S. A recurrent phospho-sumoyl switch in transcriptional repression and beyond.  Mol Cell. 2006;  23 779-786
• 62 Hardeland U, Steinacher R, Jiricny J, Schar P. Modification of the human thymine-DNA glycosylase by ubiquitin-like proteins facilitates enzymatic turnover.  Embo J. 2002;  21 1456-1464
• 63 Steinacher R, Schar P. Functionality of human thymine DNA glycosylase requires SUMO-regulated changes in protein conformation.  Curr Biol. 2005;  15 616-623
• 64 Gill G. Something about SUMO inhibits transcription.  Curr Opin Genet Dev. 2005;  15 536-541
• 65 Yang SH, Sharrocks AD. SUMO promotes HDAC-mediated transcriptional repression.  Mol Cell. 2004;  13 611-617
• 66 Girdwood D, Bumpass D, Vaughan OA. et al . P300 transcriptional repression is mediated by SUMO modification.  Mol Cell. 2003;  11 1043-1054
• 67 Shiio Y, Eisenman RN. Histone sumoylation is associated with transcriptional repression.  Proc Natl Acad Sci USA. 2003;  100 13225-13230
• 68 Bouras T, Fu M, Sauve AA. et al . 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
• 69 Gregoire S, Yang XJ. Association with class IIa histone deacetylases upregulates the sumoylation of MEF2 transcription factors.  Mol Cell Biol. 2005;  25 2273-2287
• 70 Sartorelli V, Caretti G. Mechanisms underlying the transcriptional regulation of skeletal myogenesis.  Curr Opin Genet Dev. 2005;  15 528-535
• 71 David G, Neptune MA, DePinho RA. SUMO-1 modification of histone deacetylase 1 (HDAC1) modulates its biological activities.  J Biol Chem. 2002;  277 23658-23663
• 72 Kirsh O, Seeler JS, Pichler A. et al . The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase.  Embo J. 2002;  21 2682-2691
• 73 Cheng J, Wang D, Wang Z, Yeh ET. SENP1 enhances androgen receptor-dependent transcription through desumoylation of histone deacetylase 1.  Mol Cell Biol. 2004;  24 6021-6028
• 74 Zhao LJ, Subramanian T, Zhou Y, Chinnadurai G. Acetylation by p300 regulates nuclear localization and function of the transcriptional corepressor CtBP2.  J Biol Chem. 2006;  281 4183-4189
• 75 Minty A, Dumont X, Kaghad M, Caput D. Covalent modification of p73alpha by SUMO-1 Two-hybrid screening with p73 identifies novel SUMO-1-interacting proteins and a SUMO-1 interaction motif.  J Biol Chem. 2000;  275 36316-36323
• 76 Song J, Durrin LK, Wilkinson TA, Krontiris TG, Chen Y. Identification of a SUMO-binding motif that recognizes SUMO-modified proteins.  Proc Natl Acad Sci USA. 2004;  101 14373-14378
• 77 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. 2005;  280 40122-40129
• 78 Goodson ML, Hong Y, Rogers R. et al . Sumo-1 modification regulates the DNA binding activity of heat shock transcription factor 2, a promyelocytic leukemia nuclear body associated transcription factor.  J Biol Chem. 2001;  276 18513-18518
• 79 Hong Y, Rogers R, Matunis MJ. et al . Regulation of heat shock transcription factor 1 by stress-induced SUMO-1 modification.  J Biol Chem. 2001;  276 40263-40267
• 80 Dobreva G, Dambacher J, Grosschedl R. SUMO modification of a novel MAR-binding protein, SATB2, modulates immunoglobulin mu gene expression.  Genes Dev. 2003;  17 3048-3061
• 81 Lehembre F, Badenhorst P, Muller S. et al . Covalent modification of the transcriptional repressor tramtrack by the ubiquitin-related protein Smt3 in Drosophila flies.  Mol Cell Biol. 2000;  20 1072-1082
• 82 Ishov AM, Sotnikov AG, Negorev D. 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. 1999;  147 221-234
• 83 Zhong S, Muller S, Ronchetti S. et al . Role of SUMO-1-modified PML in nuclear body formation.  Blood. 2000;  95 2748-2752
• 84 Zhong S, Salomoni P, Pandolfi PP. The transcriptional role of PML and the nuclear body.  Nature cell biology. 2000;  2 E85-E90
• 85 Boisvert FM, Kruhlak MJ, Box AK, Hendzel MJ, Bazett-Jones DP. The transcription coactivator CBP is a dynamic component of the promyelocytic leukemia nuclear body.  J Cell Biol. 2001;  152 1099-1106
• 86 Best JL, Ganiatsas S, Agarwal S. et al . SUMO-1 protease-1 regulates gene transcription through PML.  Mol Cell. 2002;  10 843-855
• 87 Kotaja N, Karvonen U, Janne OA, Palvimo JJ. PIAS proteins modulate transcription factors by functioning as SUMO-1 ligases.  Mol Cell Biol. 2002;  22 5222-5234
• 88 Melloul D, Marshak S, Cerasi E. Regulation of insulin gene transcription.  Diabetologia. 2002;  45 309-326
• 89 Iniguez-Lluhi JA, Pearce D. A common motif within the negative regulatory regions of multiple factors inhibits their transcriptional synergy.  Mol Cell Biol. 2000;  20 6040-6050
• 90 Holmstrom S, Van Antwerp ME, Iniguez-Lluhi JA. Direct and distinguishable inhibitory roles for SUMO isoforms in the control of transcriptional synergy.  Proc Natl Acad Sci USA. 2003;  100 15758-15763
• 91 Takimoto GS, Tung L, Abdel-Hafiz H. et al . Functional properties of the N-terminal region of progesterone receptors and their mechanistic relationship to structure.  J Steroid Biochem Mol Biol. 2003;  85 209-219
• 92 Ohlsson H, Karlsson K, Edlund T. IPF1, a homeodomain-containing transactivator of the insulin gene.  Embo J. 1993;  12 4251-4259
• 93 Watada H, Kajimoto Y, Miyagawa J. et al . PDX-1 induces insulin and glucokinase gene expressions in alphaTC1 clone 6 cells in the presence of betacellulin.  Diabetes. 1996;  45 1826-1831
• 94 Waeber G, Thompson N, Nicod P, Bonny C. Transcriptional activation of the GLUT2 gene by the IPF-1/STF-1/IDX-1 homeobox factor.  Mol Endocrinol. 1996;  10 1327-1334
• 95 Carty MD, Lillquist JS, Peshavaria M, Stein R, Soeller WC. Identification of cis- and trans-active factors regulating human islet amyloid polypeptide gene expression in pancreatic beta-cells.  J Biol Chem. 1997;  272 11986-11993
• 96 Macfarlane WM, MacKinnon CM, Felton-Edkins ZA. et al . Glucose stimulates translocation of the homeodomain transcription factor PDX1 from the cytoplasm to the nucleus in pancreatic beta-cells.  J Biol Chem. 1999;  274 1011-1016
• 97 Kishi A, Nakamura T, Nishio Y, Maegawa H, Kashiwagi A. Sumoylation of Pdx1 is associated with its nuclear localization and insulin gene activation.  Am J Physiol Endocrinol Metab. 2003;  284 E830-E840
• 98 Mosley AL, Corbett JA, Ozcan S. Glucose regulation of insulin gene expression requires the recruitment of p300 by the beta-cell-specific transcription factor Pdx-1.  Mol Endocrinol. 2004;  18 2279-2290
• 99 Stanojevic V, Habener JF, Thomas MK. Pancreas duodenum homeobox-1 transcriptional activation requires interactions with p300.  Endocrinology. 2004;  145 2918-2928
• 100 Mosley AL, Ozcan S. The pancreatic duodenal homeobox-1 protein (Pdx-1) interacts with histone deacetylases Hdac-1 and Hdac-2 on low levels of glucose.  J Biol Chem. 2004;  279 54241-54247
• 101 Olbrot M, Rud J, Moss LG, Sharma A. Identification of beta-cell-specific insulin gene transcription factor RIPE3b1 as mammalian MafA.  Proc Natl Acad Sci USA. 2002;  99 6737-6742
• 102 Saeki K, Zhu M, Kubosaki A. et al . Targeted disruption of the protein tyrosine phosphatase-like molecule IA-2 results in alterations in glucose tolerance tests and insulin secretion.  Diabetes. 2002;  51 1842-1850
• 103 Harashima S, Clark A, Christie MR, Notkins AL. The dense core transmembrane vesicle protein IA-2 is a regulator of vesicle number and insulin secretion.  Proc Natl Acad Sci USA. 2005;  102 8704-8709
• 104 Trajkovski M, Mziaut H, Altkruger A. et al . Nuclear translocation of an ICA512 cytosolic fragment couples granule exocytosis and insulin expression in β-cells.  J Cell Biol. 2004;  167 1063-1074
• 105 Mziaut H, Trajkovski M, Kersting S. et al . Synergy of glucose and growth hormone signalling in islet cells through ICA512 and STAT5.  Nature cell biology. 2006;  8 435-445
• 106 Lan MS, Lu J, Goto Y, Notkins AL. Molecular cloning and identification of a receptor-type protein tyrosine phosphatase, IA-2, from human insulinoma.  DNA Cell Biol. 1994;  13 505-514
• 107 Magistrelli G, Toma S, Isacchi A. Substitution of two variant residues in the protein tyrosine phosphatase-like PTP35/IA-2 sequence reconstitutes catalytic activity.  Biochem Biophys Res Commun. 1996;  227 581-588
• 108 Matsuoka T, Zhao L, Stein R. The DNA binding activity of the RIPE3b1 transcription factor of insulin appears to be influenced by tyrosine phosphorylation.  J Biol Chem. 2001;  276 22071-22076
• 109 Guo D, Li M, Zhang Y. et al . A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes.  Nat Genet. 2004;  36 837-841
• 110 Park Y, Park S, Kang J, Yang S, Kim D. Assessing the validity of the association between the SUMO4 M55 V variant and risk of type 1 diabetes.  Nat Genet. 2005;  37 112 , Authors’ reply: 112-113
• 111 Owerbach D, MacKay EM, Yeh ET, Gabbay KH, Bohren KM. A proline-90 residue unique to SUMO-4 prevents maturation and sumoylation.  Biochem Biophys Res Commun. 2005;  337 517-520
• 112 Li M, Guo D, Isales CM. et al . SUMO wrestling with type 1 diabetes.  J Mol Med. 2005;  83 504-513
• 113 Kosoy R, Concannon P. Functional variants in SUMO4, TAB2, and NFkappaB and the risk of type 1 diabetes.  Genes Immun. 2005;  6 231-235
• 114 Smyth DJ, Howson JM, Lowe CE. et al . Assessing the validity of the association between the SUMO4 M55 V variant and risk of type 1 diabetes.  Nat Genet. 2005;  37 110-111 , Authors’ reply: 112-113
• 115 Qu H, Bharaj B, Liu XQ. et al . Assessing the validity of the association between the SUMO4 M55 V variant and risk of type 1 diabetes.  Nat Genet. 2005;  37 111-112 , Authors’ reply: 112-113

Correspondence