UBE2I explained

SUMO-conjugating enzyme UBC9 is an enzyme that in humans is encoded by the UBE2I gene.^[1] It is also sometimes referred to as "ubiquitin conjugating enzyme E2I" or "ubiquitin carrier protein 9", even though these names do not accurately describe its function.

Expression

Four alternatively spliced transcript variants encoding the same protein have been found for this gene.^[2]

Function

The UBC9 protein encoded by the UBE2I gene constitutes a core machinery in the cell's sumoylation pathway. Sumoylation is a process in which a Small Ubiquitin-like MOdifier (SUMO) is covalently attached to other proteins in order to modify their behaviour. For example, sumoylation may affect a protein's localization in the cell, its ability to interact with other proteins or DNA.

UBC9 performs the third step in the sumoylation life cycle: the conjugation step. When SUMO protein precursors are first expressed, they first undergo a maturation step in which the four C-terminal amino acids are removed, revealing a di-glycine motif. In a second step, an E1 activating complex binds to SUMO at its di-glycine and passes it on to the E2 protein Ubc9, where it forms a thioester bond with a cysteine residue within Ubc9's catalytic pocket. The loaded Ubc9 is now ready to perform the sumoylation of its various target proteins (also called substrates). It recognizes a particular motif of amino acid residues in these substrates: A large hydrophobic residue, followed by a lysine, followed by a spacer, followed by an acidic residue. This motif is usually described in shorthand as ΨKxD/E. The central lysine within the substrate's recognition motif is inserted into the catalytic pocket. There the carboxyl terminus of SUMO's di-glycine forms a peptide bond with the ε-amino group of the lysine. This process can be assisted by an E3 ligase protein.

The sumoylation process is reversible. SENP proteases can remove SUMO from sumoylated proteins, freeing it to be used in further sumoylation reactions.

Clinical significance relevance

The protein UBC9 encoded by the UBE2I gene has been shown to be targeted by multiple viruses, including HIV and HPV. It has been hypothesized that these viruses hijack UBC9 to serve their own purposes.^[3]

Interactions

UBE2I has been shown to interact with:

• ATF2,^[4]
• Androgen receptor,^[5]
• BLMH,^[6]
• DACH1,^[7]
• DNMT3A,^[8]
• DNMT3B,^[9]
• DAXX,^[10]
• ETS1,^[11]
• FHIT,^[12]
• IPO13,^[13]
• MAP3K1 and
• MITF,^[14]
• P53,^{[15] [16]}
• PIAS1,^{[17] [18] [19]}
• PIAS2,^{[20] [17]}
• RAD51,^{[21] [22]}
• RANBP2,^{[23] [24]}
• RANGAP1,^[23]
• SAE2,^{[25] [23]}
• SALL1,^[26]
• SUMO1,^{[21] [27] [23] [28]}
• TCF3,^[29]
• TNFRSF1A,^[30]
• TOP1,^[31] and
• WT1.^[32]

References

• Kovalenko OV, Plug AW, Haaf T, Gonda DK, Ashley T, Ward DC, Radding CM, Golub EI . Mammalian ubiquitin-conjugating enzyme Ubc9 interacts with Rad51 recombination protein and localizes in synaptonemal complexes . Proc. Natl. Acad. Sci. U.S.A. . 93 . 7 . 2958–63 . 1996 . 8610150 . 39742 . 10.1073/pnas.93.7.2958 . 1996PNAS...93.2958K . free .
• Jiang W, Koltin Y . Two-hybrid interaction of a human UBC9 homolog with centromere proteins of Saccharomyces cerevisiae . Mol. Gen. Genet. . 251 . 2 . 153–60 . 1996 . 8668125 . 10.1007/s004380050152 .
• Yasugi T, Howley PM . Identification of the structural and functional human homolog of the yeast ubiquitin conjugating enzyme UBC9 . Nucleic Acids Res. . 24 . 11 . 2005–10 . 1996 . 8668529 . 145898 . 10.1093/nar/24.11.2005 .
• Göttlicher M, Heck S, Doucas V, Wade E, Kullmann M, Cato AC, Evans RM, Herrlich P . Interaction of the Ubc9 human homologue with c-Jun and with the glucocorticoid receptor . Steroids . 61 . 4 . 257–62 . 1996 . 8733011 . 10.1016/0039-128X(96)00032-3 . 11608979 .
• Schneikert J, Peterziel H, Defossez PA, Klocker H, de Launoit Y, Cato AC . Androgen receptor-Ets protein interaction is a novel mechanism for steroid hormone-mediated down-modulation of matrix metalloproteinase expression . J. Biol. Chem. . 271 . 39 . 23907–13 . 1996 . 8798622 . 10.1074/jbc.271.39.23907 . free .
• Wang ZY, Qiu QQ, Seufert W, Taguchi T, Testa JR, Whitmore SA, Callen DF, Welsh D, Shenk T, Deuel TF . Molecular cloning of the cDNA and chromosome localization of the gene for human ubiquitin-conjugating enzyme 9 . J. Biol. Chem. . 271 . 40 . 24811–6 . 1996 . 8798754 . 10.1074/jbc.271.40.24811 . free .
• Hateboer G, Hijmans EM, Nooij JB, Schlenker S, Jentsch S, Bernards R . mUBC9, a novel adenovirus E1A-interacting protein that complements a yeast cell cycle defect . J. Biol. Chem. . 271 . 42 . 25906–11 . 1996 . 8824223 . 10.1074/jbc.271.42.25906 . 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 . 1997 . 8921390 . 10.1006/geno.1996.0540 .
• Tachibana M, Iwata N, Watanabe A, Nobukuni Y, Ploplis B, Kajigaya S . Assignment of the gene for a ubiquitin-conjugating enzyme (UBE2I) to human chromosome band 16p13.3 by in situ hybridization . Cytogenet. Cell Genet. . 75 . 4 . 222–3 . 1997 . 9067428 . 10.1159/000134487 .
• Masson M, Menissier-de Murcia J, Mattei MG, de Murcia G, Niedergang CP . Poly(ADP-ribose) polymerase interacts with a novel human ubiquitin conjugating enzyme: hUbc9 . Gene . 190 . 2 . 287–96 . 1997 . 9197546 . 10.1016/S0378-1119(97)00015-2 .
• Yasugi T, Vidal M, Sakai H, Howley PM, Benson JD . Two classes of human papillomavirus type 16 E1 mutants suggest pleiotropic conformational constraints affecting E1 multimerization, E2 interaction, and interaction with cellular proteins . J. Virol. . 71 . 8 . 5942–51 . 1997 . 9223484 . 191850 . 10.1128/JVI.71.8.5942-5951.1997.
• Becker K, Schneider P, Hofmann K, Mattmann C, Tschopp J . Interaction of Fas(Apo-1/CD95) with proteins implicated in the ubiquitination pathway . FEBS Lett. . 412 . 1 . 102–6 . 1997 . 9257699 . 10.1016/S0014-5793(97)00758-8 . 689407 . free .
• Tong H, Hateboer G, Perrakis A, Bernards R, Sixma TK . Crystal structure of murine/human Ubc9 provides insight into the variability of the ubiquitin-conjugating system . J. Biol. Chem. . 272 . 34 . 21381–7 . 1997 . 9261152 . 10.1074/jbc.272.34.21381 . 10.1.1.531.2567 . 45098033 . free .
• Hahn SL, Wasylyk B, Criqui-Filipe P, Criqui P . Modulation of ETS-1 transcriptional activity by huUBC9, a ubiquitin-conjugating enzyme . Oncogene . 15 . 12 . 1489–95 . 1997 . 9333025 . 10.1038/sj.onc.1201301 . 26170389 .
• Hu G, Zhang S, Vidal M, Baer JL, Xu T, Fearon ER . Mammalian homologs of seven in absentia regulate DCC via the ubiquitin–proteasome pathway . Genes Dev. . 11 . 20 . 2701–14 . 1997 . 9334332 . 316613 . 10.1101/gad.11.20.2701 .
• Firestein R, Feuerstein N . Association of activating transcription factor 2 (ATF2) with the ubiquitin-conjugating enzyme hUBC9. Implication of the ubiquitin/proteasome pathway in regulation of ATF2 in T cells . J. Biol. Chem. . 273 . 10 . 5892–902 . 1998 . 9488727 . 10.1074/jbc.273.10.5892 . free .
• Joanisse DR, Inaguma Y, Tanguay RM . Cloning and developmental expression of a nuclear ubiquitin-conjugating enzyme (DmUbc9) that interacts with small heat shock proteins in Drosophila melanogaster . Biochem. Biophys. Res. Commun. . 244 . 1 . 102–9 . 1998 . 9514881 . 10.1006/bbrc.1998.8214 .
• Saltzman A, Searfoss G, Marcireau C, Stone M, Ressner R, Munro R, Franks C, D'Alonzo J, Tocque B, Jaye M, Ivashchenko Y . hUBC9 associates with MEKK1 and type I TNF-alpha receptor and stimulates NFkappaB activity . FEBS Lett. . 425 . 3 . 431–5 . 1998 . 9563508 . 10.1016/S0014-5793(98)00287-7 . 84816080 . free .
• Koldamova RP, Lefterov IM, DiSabella MT, Lazo JS . An evolutionarily conserved cysteine protease, human bleomycin hydrolase, binds to the human homologue of ubiquitin-conjugating enzyme 9 . Mol. Pharmacol. . 54 . 6 . 954–61 . 1999 . 9855622 . 10.1124/mol.54.6.954.

Notes and References

1. Watanabe TK, Fujiwara T, Kawai A, Shimizu F, Takami S, Hirano H, Okuno S, Ozaki K, Takeda S, Shimada Y, Nagata M, Takaichi A, Takahashi E, Nakamura Y, Shin S . Cloning, expression, and mapping of UBE2I, a novel gene encoding a human homologue of yeast ubiquitin-conjugating enzymes which are critical for regulating the cell cycle . Cytogenet Cell Genet . 72 . 1 . 86–9 . March 1996 . 8565643 . 10.1159/000134169 .
2. Web site: Entrez Gene: UBE2I ubiquitin-conjugating enzyme E2I (UBC9 homolog, yeast).
3. Varadaraj A, Mattoscio D, Chiocca S . SUMO Ubc9 enzyme as a viral target . IUBMB Life . 66 . 1 . 27–33 . Jan 2014 . 24395713 . 10.1002/iub.1240 . 42047371 . varadaraj2014 .
4. Firestein R, Feuerstein N . Association of activating transcription factor 2 (ATF2) with the ubiquitin-conjugating enzyme hUBC9. Implication of the ubiquitin/proteasome pathway in regulation of ATF2 in T cells . J. Biol. Chem. . 273 . 10 . 5892–902 . March 1998 . 9488727 . 10.1074/jbc.273.10.5892. free .
5. Poukka H, Aarnisalo P, Karvonen U, Palvimo JJ, Jänne OA . Ubc9 interacts with the androgen receptor and activates receptor-dependent transcription . J. Biol. Chem. . 274 . 27 . 19441–6 . July 1999 . 10383460 . 10.1074/jbc.274.27.19441. free .
6. Koldamova RP, Lefterov IM, DiSabella MT, Lazo JS . An evolutionarily conserved cysteine protease, human bleomycin hydrolase, binds to the human homologue of ubiquitin-conjugating enzyme 9 . Mol. Pharmacol. . 54 . 6 . 954–61 . Dec 1998 . 9855622 . 10.1124/mol.54.6.954.
7. Machon O, Backman M, Julin K, Krauss S . Yeast two-hybrid system identifies the ubiquitin-conjugating enzyme mUbc9 as a potential partner of mouse Dac . Mech. Dev. . 97 . 1–2 . 3–12 . October 2000 . 11025202 . 10.1016/s0925-4773(00)00402-0. 14154139 . free .
8. Ling Y, Sankpal UT, Robertson AK, McNally JG, Karpova T, Robertson KD . Modification of de novo DNA methyltransferase 3a (Dnmt3a) by SUMO-1 modulates its interaction with histone deacetylases (HDACs) and its capacity to repress transcription . Nucleic Acids Res. . 2004 . 32 . 2 . 598–610 . 14752048 . 373322 . 10.1093/nar/gkh195 .
9. 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 . Biochem. Biophys. Res. Commun. . 289 . 4 . 862–8 . Dec 2001 . 11735126 . 10.1006/bbrc.2001.6057 .
10. Ryu SW, Chae SK, Kim E . Interaction of Daxx, a Fas binding protein, with sentrin and Ubc9 . Biochem. Biophys. Res. Commun. . 279 . 1 . 6–10 . Dec 2000 . 11112409 . 10.1006/bbrc.2000.3882 .
11. Hahn SL, Wasylyk B, Criqui-Filipe P, Criqui P . Modulation of ETS-1 transcriptional activity by huUBC9, a ubiquitin-conjugating enzyme . Oncogene . 15 . 12 . 1489–95 . September 1997 . 9333025 . 10.1038/sj.onc.1201301 . 26170389 .
12. Shi Y, Zou M, Farid NR, Paterson MC . Association of FHIT (fragile histidine triad), a candidate tumour suppressor gene, with the ubiquitin-conjugating enzyme hUBC9 . Biochem. J. . 352 . 2. 443–8 . Dec 2000 . 11085938 . 1221476 . 10.1042/0264-6021:3520443.
13. Mingot JM, Kostka S, Kraft R, Hartmann E, Görlich D . Importin 13: a novel mediator of nuclear import and export . EMBO J. . 20 . 14 . 3685–94 . July 2001 . 11447110 . 125545 . 10.1093/emboj/20.14.3685 .
14. Xu W, Gong L, Haddad MM, Bischof O, Campisi J, Yeh ET, Medrano EE . Regulation of microphthalmia-associated transcription factor MITF protein levels by association with the ubiquitin-conjugating enzyme hUBC9 . Exp. Cell Res. . 255 . 2 . 135–43 . March 2000 . 10694430 . 10.1006/excr.2000.4803 .
15. Gallagher WM, Argentini M, Sierra V, Bracco L, Debussche L, Conseiller E . MBP1: a novel mutant p53-specific protein partner with oncogenic properties . Oncogene . 18 . 24 . 3608–16 . June 1999 . 10380882 . 10.1038/sj.onc.1202937 . free .
16. 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 . 108 . 3 . 345–56 . February 2002 . 11853669 . 10.1016/s0092-8674(02)00630-x. 15512250 . free .
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18. 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. . 21 . 19 . 5206–15 . October 2002 . 12356736 . 129032 . 10.1093/emboj/cdf510.
19. Kahyo T, Nishida T, Yasuda H . Involvement of PIAS1 in the sumoylation of tumor suppressor p53 . Mol. Cell . 8 . 3 . 713–8 . September 2001 . 11583632 . 10.1016/s1097-2765(01)00349-5. free .
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21. 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 . 183–186 . October 1996 . 8921390 . 10.1006/geno.1996.0540.
22. Kovalenko OV, Plug AW, Haaf T, Gonda DK, Ashley T, Ward DC, Radding CM, Golub EI . Mammalian ubiquitin-conjugating enzyme Ubc9 interacts with Rad51 recombination protein and localizes in synaptonemal complexes . Proc. Natl. Acad. Sci. U.S.A. . 93 . 7 . 2958–63 . April 1996 . 8610150 . 39742 . 10.1073/pnas.93.7.2958. 1996PNAS...93.2958K . free .
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24. Zhang H, Saitoh H, Matunis MJ . Enzymes of the SUMO modification pathway localize to filaments of the nuclear pore complex . Mol. Cell. Biol. . 22 . 18 . 6498–508 . September 2002 . 12192048 . 135644 . 10.1128/mcb.22.18.6498-6508.2002.
25. Knipscheer P, Flotho A, Klug H, Olsen JV, van Dijk WJ, Fish A, Johnson ES, Mann M, Sixma TK, Pichler A . Ubc9 sumoylation regulates SUMO target discrimination . Mol. Cell . 31 . 3 . 371–82 . August 2008 . 18691969 . 10.1016/j.molcel.2008.05.022 . free .
26. Netzer C, Bohlander SK, Rieger L, Müller S, Kohlhase J . Interaction of the developmental regulator SALL1 with UBE2I and SUMO-1 . Biochem. Biophys. Res. Commun. . 296 . 4 . 870–6 . August 2002 . 12200128 . 10.1016/s0006-291x(02)02003-x.
27. 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. . 275 . 46 . 36316–23 . November 2000 . 10961991 . 10.1074/jbc.M004293200 . free .
28. 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 .
29. Huggins GS, Chin MT, Sibinga NE, Lee SL, Haber E, Lee ME . Characterization of the mUBC9-binding sites required for E2A protein degradation . J. Biol. Chem. . 274 . 40 . 28690–6 . October 1999 . 10497239 . 10.1074/jbc.274.40.28690. free .
30. Saltzman A, Searfoss G, Marcireau C, Stone M, Ressner R, Munro R, Franks C, D'Alonzo J, Tocque B, Jaye M, Ivashchenko Y . hUBC9 associates with MEKK1 and type I TNF-alpha receptor and stimulates NFkappaB activity . FEBS Lett. . 425 . 3 . 431–5 . April 1998 . 9563508 . 10.1016/s0014-5793(98)00287-7. 84816080 . free .
31. Leroy Liu . Mao Y, Sun M, Desai SD, Liu LF . SUMO-1 conjugation to topoisomerase I: A possible repair response to topoisomerase-mediated DNA damage . Proc. Natl. Acad. Sci. U.S.A. . 97 . 8 . 4046–51 . April 2000 . 10759568 . 18143 . 10.1073/pnas.080536597 . 2000PNAS...97.4046M . free .
32. Wang ZY, Qiu QQ, Seufert W, Taguchi T, Testa JR, Whitmore SA, Callen DF, Welsh D, Shenk T, Deuel TF . Molecular cloning of the cDNA and chromosome localization of the gene for human ubiquitin-conjugating enzyme 9 . J. Biol. Chem. . 271 . 40 . 24811–6 . October 1996 . 8798754 . 10.1074/jbc.271.40.24811. free .