SUMO1 explained

Small ubiquitin-related modifier 1 is a protein that in humans is encoded by the SUMO1 gene.^{[1] [2]}

Function

This gene encodes a protein that is a member of the SUMO (small ubiquitin-like modifier) protein family. It is a ubiquitin-like protein and functions in a manner similar to ubiquitin in that it is bound to target proteins as part of a post-translational modification system. However, unlike ubiquitin, which is primarily associated with targeting proteins for proteasomal degradation, SUMO1 is involved in a variety of cellular processes, such as nuclear transport, transcriptional regulation, apoptosis, and protein stability. It is not active until the last four amino acids of the carboxy-terminus have been cleaved off. Several pseudogenes have been reported for this gene. Alternate transcriptional splice variants encoding different isoforms have been characterized.^[3]

Most cleft genes have a sumoylation component.^[4] Analysis of chromosomal anomalies in patients has led to the identification and confirmation of SUMO1 as a cleft lip and palate locus.^[5]

Interactions

Small ubiquitin-related modifier 1 has been shown to interact with:

• C22orf25,^[6]
• DAXX,^{[7] [8] [9]}
• DNMT3B,^[10]
• P53,^[9]
• PIAS1,^{[11] [12]}
• PML,^{[7] [13]}
• SAE2,^{[14] [15]}
• SP1,^[16]
• TDG,^{[17] [18]}
• TNFRSF1A,^{[2] [19]}
• TNFRSF6,^{[2] [8]}
• TOP2A,
• TOP2B,^[20] and
• UBE2I,^{[17] [14] [21] [22]}

Role in the heart

Heart failure is a process by which the heart’s pumping ability is significantly weakened, so that the body is unable to get adequate circulation. A weakened heart results in symptoms of fatigue, decreased exercise tolerance and shortness of breath. Patients with heart failure have a significantly increased risk of death compared to people with normal heart function. Heart failure is a major public health concern, as its incidence is on the rise worldwide, and is a leading cause of death in developed nations ^[23]

SUMO 1 is a key component in cardiac function, since it helps regulate calcium homeostasis in the mitochondria of heart cells. SUMO 1 is associated with another essential cardiac protein called sarco/endoplasmic reticulum Ca2+ ATPase, or SERCA2A. SERCA is a transmembrane protein located in the sarcoplasmic reticulum of cardiac cells. Its main function is to regulate the discharge and uptake of intracellular calcium between the cytosol and the lumen of the sarcoplasmic reticulum. Calcium is an essential factor for the development of cardiac myocyte contraction and relaxation. Thus, the management of intracellular calcium homeostasis by SERCA2A is critical for overall cardiac performance.^[24] Normally, SUMO 1 activates and stabilizes SERCA2A by binding at lysine resides 480 and 585. The interaction between SUMO 1 and SERCA2A is crucial for regulating calcium levels inside cardiac myocytes. Reduction in SUMO 1 protein reduces SERCA2A, and thus efficient calcium handling in patients with failing hearts.^[25]

As a drug target

SUMO 1 may be an important therapeutic target to help improve cardiac performance in patients with heart failure. In a mouse model, the introduction of SUMO 1 through gene therapy was associated with improved activity of SERCA2A, which resulted in improved cardiac function through an augmentation of cardiac contractility. Furthermore, overexpression of SUMO 1 resulted in accelerated calcium uptake, providing further evidence regarding its importance in maintaining adequate calcium levels in heart cells.

See also

• SENP6

Further reading

• Cookson MR . Pathways to Parkinsonism . Neuron . 37 . 1 . 7–10 . January 2003 . 12526767 . 10.1016/S0896-6273(02)01166-2 . 14513509 . free .
• Boddy MN, Howe K, Etkin LD, Solomon E, Freemont PS . 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 . 5 . 971–82 . September 1996 . 8806687 .
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Research . 6 . 9 . 791–806 . September 1996 . 8889548 . 10.1101/gr.6.9.791 . free .
• Shen Z, Pardington-Purtymun PE, Comeaux JC, Moyzis RK, Chen DJ . Associations of UBE2I with RAD52, UBL1, p53, and RAD51 proteins in a yeast two-hybrid system . Genomics . 37 . 2 . 183–6 . October 1996 . 8921390 . 10.1006/geno.1996.0540 .
• 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 . The Journal of Cell Biology . 135 . 6 Pt 1 . 1457–70 . December 1996 . 8978815 . 2133973 . 10.1083/jcb.135.6.1457 .
• 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 . 1 . 97–107 . January 1997 . 9019411 . 10.1016/S0092-8674(00)81862-0 . 17819277 . free .
• Lapenta V, Chiurazzi P, van der Spek P, Pizzuti A, Hanaoka F, Brahe C . SMT3A, a human homologue of the S. cerevisiae SMT3 gene, maps to chromosome 21qter and defines a novel gene family . Genomics . 40 . 2 . 362–6 . March 1997 . 9119407 . 10.1006/geno.1996.4556 .
• Kamitani T, Nguyen HP, Yeh ET . Preferential modification of nuclear proteins by a novel ubiquitin-like molecule . The Journal of Biological Chemistry . 272 . 22 . 14001–4 . May 1997 . 9162015 . 10.1074/jbc.272.22.14001 . free .
• Mahajan R, Gerace L, Melchior F . Molecular characterization of the SUMO-1 modification of RanGAP1 and its role in nuclear envelope association . The Journal of Cell Biology . 140 . 2 . 259–70 . January 1998 . 9442102 . 2132567 . 10.1083/jcb.140.2.259 .
• Howe K, Williamson J, Boddy N, Sheer D, Freemont P, Solomon E . The ubiquitin-homology gene PIC1: characterization of mouse (Pic1) and human (UBL1) genes and pseudogenes . Genomics . 47 . 1 . 92–100 . January 1998 . 9465300 . 10.1006/geno.1997.5091 .
• Bayer P, Arndt A, Metzger S, Mahajan R, Melchior F, Jaenicke R, Becker J . Structure determination of the small ubiquitin-related modifier SUMO-1 . Journal of Molecular Biology . 280 . 2 . 275–86 . July 1998 . 9654451 . 10.1006/jmbi.1998.1839 .
• Desterro JM, Rodriguez MS, Hay RT . SUMO-1 modification of IkappaBalpha inhibits NF-kappaB activation . Molecular Cell . 2 . 2 . 233–9 . August 1998 . 9734360 . 10.1016/S1097-2765(00)80133-1 .
• Juo P, Kuo CJ, Yuan J, Blenis J . Essential requirement for caspase-8/FLICE in the initiation of the Fas-induced apoptotic cascade . Current Biology . 8 . 18 . 1001–8 . September 1998 . 9740801 . 10.1016/S0960-9822(07)00420-4 . 18129508 . free .
• Kamitani T, Kito K, Nguyen HP, Wada H, Fukuda-Kamitani T, Yeh ET . Identification of three major sentrinization sites in PML . The Journal of Biological Chemistry . 273 . 41 . 26675–82 . October 1998 . 9756909 . 10.1074/jbc.273.41.26675 . free .
• Duprez E, Saurin AJ, Desterro JM, Lallemand-Breitenbach V, Howe K, Boddy MN, Solomon E, de Thé H, Hay RT, Freemont PS . SUMO-1 modification of the acute promyelocytic leukaemia protein PML: implications for nuclear localisation . Journal of Cell Science . 112 (Pt 3) . 3 . 381–93 . February 1999 . 10.1242/jcs.112.3.381 . 9885291 .
• Chen A, Mannen H, Li SS . Characterization of mouse ubiquitin-like SMT3A and SMT3B cDNAs and gene/pseudogenes . Biochemistry and Molecular Biology International . 46 . 6 . 1161–74 . December 1998 . 9891849 . 10.1080/15216549800204722 . 45939730 . free .
• Okuma T, Honda R, Ichikawa G, Tsumagari N, Yasuda H . In vitro SUMO-1 modification requires two enzymatic steps, E1 and E2 . Biochemical and Biophysical Research Communications . 254 . 3 . 693–8 . January 1999 . 9920803 . 10.1006/bbrc.1998.9995 .
• Liou ML, Liou HC . The ubiquitin-homology protein, DAP-1, associates with tumor necrosis factor receptor (p60) death domain and induces apoptosis . The Journal of Biological Chemistry . 274 . 15 . 10145–53 . April 1999 . 10187798 . 10.1074/jbc.274.15.10145 . free .

Notes and References

1. Shen Z, Pardington-Purtymun PE, Comeaux JC, Moyzis RK, Chen DJ . UBL1, a human ubiquitin-like protein associating with human RAD51/RAD52 proteins . Genomics . 36 . 2 . 271–9 . September 1996 . 8812453 . 10.1006/geno.1996.0462 .
2. Okura T, Gong L, Kamitani T, Wada T, Okura I, Wei CF, Chang HM, Yeh ET . Protection against Fas/APO-1- and tumor necrosis factor-mediated cell death by a novel protein, sentrin . Journal of Immunology . 157 . 10 . 4277–81 . November 1996 . 10.4049/jimmunol.157.10.4277 . 8906799 . 38606511 . free .
3. Web site: Entrez Gene: SUMO1 SMT3 suppressor of mif two 3 homolog 1 (S. cerevisiae).
4. Pauws E, Stanier P . FGF signalling and SUMO modification: new players in the aetiology of cleft lip and/or palate . Trends in Genetics . 23 . 12 . 631–40 . December 2007 . 17981355 . 10.1016/j.tig.2007.09.002 .
5. Dixon MJ, Marazita ML, Beaty TH, Murray JC (2011). "Cleft lip and palate: understanding genetic and environmental influences". Nature Reviews Genetics (12) 167-178.
6. Web site: Molecular Interaction Database. dead. https://web.archive.org/web/20060506110418/http://mint.bio.uniroma2.it/mint/Welcome.do. 2006-05-06.
7. Lin DY, Shih HM . Essential role of the 58-kDa microspherule protein in the modulation of Daxx-dependent transcriptional repression as revealed by nucleolar sequestration . The Journal of Biological Chemistry . 277 . 28 . 25446–56 . July 2002 . 11948183 . 10.1074/jbc.M200633200 . free .
8. Ryu SW, Chae SK, Kim E . Interaction of Daxx, a Fas binding protein, with sentrin and Ubc9 . Biochemical and Biophysical Research Communications . 279 . 1 . 6–10 . December 2000 . 11112409 . 10.1006/bbrc.2000.3882 .
9. Ivanchuk SM, Mondal S, Rutka JT . p14ARF interacts with DAXX: effects on HDM2 and p53 . Cell Cycle . 7 . 12 . 1836–50 . June 2008 . 18583933 . 10.4161/cc.7.12.6025 . free .
10. Kang ES, Park CW, Chung JH . Dnmt3b, de novo DNA methyltransferase, interacts with SUMO-1 and Ubc9 through its N-terminal region and is subject to modification by SUMO-1 . Biochemical and Biophysical Research Communications . 289 . 4 . 862–8 . December 2001 . 11735126 . 10.1006/bbrc.2001.6057 .
11. Lee BH, Yoshimatsu K, Maeda A, Ochiai K, Morimatsu M, Araki K, Ogino M, Morikawa S, Arikawa J . Association of the nucleocapsid protein of the Seoul and Hantaan hantaviruses with small ubiquitin-like modifier-1-related molecules . Virus Research . 98 . 1 . 83–91 . December 2003 . 14609633 . 10.1016/j.virusres.2003.09.001 .
12. Kahyo T, Nishida T, Yasuda H . Involvement of PIAS1 in the sumoylation of tumor suppressor p53 . Molecular Cell . 8 . 3 . 713–8 . September 2001 . 11583632 . 10.1016/S1097-2765(01)00349-5 . free .
13. Kamitani T, Nguyen HP, Kito K, Fukuda-Kamitani T, Yeh ET . Covalent modification of PML by the sentrin family of ubiquitin-like proteins . The Journal of Biological Chemistry . 273 . 6 . 3117–20 . February 1998 . 9452416 . 10.1074/jbc.273.6.3117 . free .
14. Tatham MH, Kim S, Yu B, Jaffray E, Song J, Zheng J, Rodriguez MS, Hay RT, Chen Y . Role of an N-terminal site of Ubc9 in SUMO-1, -2, and -3 binding and conjugation . Biochemistry . 42 . 33 . 9959–69 . August 2003 . 12924945 . 10.1021/bi0345283 .
15. 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 Letters . 448 . 1 . 185–9 . April 1999 . 10217437 . 10.1016/S0014-5793(99)00367-1 . 7756078 .
16. Wang YT, Chuang JY, Shen MR, Yang WB, Chang WC, Hung JJ . Sumoylation of specificity protein 1 augments its degradation by changing the localization and increasing the specificity protein 1 proteolytic process . Journal of Molecular Biology . 380 . 5 . 869–85 . July 2008 . 18572193 . 10.1016/j.jmb.2008.05.043 .
17. 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 . The Journal of Biological Chemistry . 275 . 46 . 36316–23 . November 2000 . 10961991 . 10.1074/jbc.M004293200 . free .
18. Hardeland U, Steinacher R, Jiricny J, Schär P . Modification of the human thymine-DNA glycosylase by ubiquitin-like proteins facilitates enzymatic turnover . The EMBO Journal . 21 . 6 . 1456–64 . March 2002 . 11889051 . 125358 . 10.1093/emboj/21.6.1456 .
19. Liou ML, Liou HC . The ubiquitin-homology protein, DAP-1, associates with tumor necrosis factor receptor (p60) death domain and induces apoptosis . The Journal of Biological Chemistry . 274 . 15 . 10145–53 . April 1999 . 10187798 . 10.1074/jbc.274.15.10145 . free .
20. Leroy Liu . Mao Y, Desai SD, Liu LF . SUMO-1 conjugation to human DNA topoisomerase II isozymes . The Journal of Biological Chemistry . 275 . 34 . 26066–73 . August 2000 . 10862613 . 10.1074/jbc.M001831200 . free .
21. Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D . Large-scale mapping of human protein-protein interactions by mass spectrometry . Molecular Systems Biology . 3 . 1 . 89 . 2007 . 17353931 . 1847948 . 10.1038/msb4100134 .
22. Shen Z, Pardington-Purtymun PE, Comeaux JC, Moyzis RK, Chen DJ . Associations of UBE2I with RAD52, UBL1, p53, and RAD51 proteins in a yeast two-hybrid system . Genomics . 37 . 2 . 183–6 . October 1996 . 8921390 . 10.1006/geno.1996.0540 .
23. Schwartz RJ, Yeh ET . Weighing in on heart failure: the role of SERCA2a SUMOylation . Circulation Research . 110 . 2 . 198–9 . 2012 . 22267837 . 10.1161/RES.0b013e318246f187 . free .
24. Periasamy M, Huke S . SERCA pump level is a critical determinant of Ca(2+)homeostasis and cardiac contractility . Journal of Molecular and Cellular Cardiology . 33 . 6 . 1053–63 . 2001 . 11444913 . 10.1006/jmcc.2001.1366 .
25. Kho C, Lee A, Jeong D, Oh JG, Chaanine AH, Kizana E, Park WJ, Hajjar RJ . SUMO1-dependent modulation of SERCA2a in heart failure . Nature . 477 . 7366 . 601–5 . 2011 . 21900893 . 3443490 . 10.1038/nature10407 . 2011Natur.477..601K .