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Gene Review

UBE2I  -  ubiquitin-conjugating enzyme E2I

Homo sapiens

Synonyms: C358B7.1, P18, SUMO-conjugating enzyme UBC9, SUMO-protein ligase, UBC9, ...
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Disease relevance of UBE2I

  • Overall, our results indicate that Ubc9 influences IE2's function and provide new information on the complex interactions that occur between herpesviruses and the sumoylation pathway [1].
  • Evaluation of interactions of human cytomegalovirus immediate-early IE2 regulatory protein with small ubiquitin-like modifiers and their conjugation enzyme Ubc9 [2].
  • The p18 gene was wild type in these 71 lung cancers, except 1 metastatic NSCLC which showed loss of heterozygosity [3].
  • To test this, we overexpressed a dominant-negative mutant of Ubc9 (Ubc9-DN) and wild-type Ubc9 (Ubc9-WT) in the MCF-7 human breast tumor cells [4].
  • HIV-1 p6 was found to interact with small ubiquitin-like modifier 1 (SUMO-1) as well as the E2 SUMO-1 transfer enzyme, Ubc9 [5].

High impact information on UBE2I

  • Crystallographic analysis of a complex between mammalian Ubc9 and a C-terminal domain of RanGAP1 at 2.5 A reveals structural determinants for recognition of consensus SUMO modification sequences found within SUMO-conjugated proteins [6].
  • However, a carboxyl-terminal fragment of Pc2 that recruits both Ubc9 and CtBP lacks E3 activity [7].
  • These properties were essential, since PIASy mutants that did not bind chromatin or failed to recruit Ubc9 were functionally inactive [8].
  • The SUMO-1-conjugating enzyme Ubc9 interacts with androgen receptor (AR), a ligand-activated transcription factor belonging to the steroid receptor superfamily [9].
  • Our studies show that UBC9 binds to TEL exclusively through the HLH domain of TEL [10].

Chemical compound and disease context of UBE2I

  • The determinant of HIV-1 gp160 for the stimulation of CTL is located in a region of high sequence variability among HIV-1 isolates, the so-called V3 loop P18 [11].

Biological context of UBE2I

  • 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 [12].
  • This gene, UBE2I, was mapped to chromosome band 16p13.3 by FISH [12].
  • The human UBC9 (h-UBC9) cDNA, (gene symbol UBE2I), contained an open reading frame of 474 nucleotides encoding 158 amino acids [12].
  • Peptides with sequences that correspond to those of the SUMO-1 conjugation sites from p53 and c-Jun both bind to a surface adjacent to the active site Cys93 of human Ubc9, which has been previously shown to include residues that demonstrate the most significant dynamics on the microsecond to millisecond time scale [13].
  • Analysis of Fhit kinetics in the presence of different fixed concentrations of Ubc9 showed that Ubc9 is an uncompetitive inhibitor [14].

Anatomical context of UBE2I

  • Using immunogold labeling of isolated nuclear envelopes, we found that Ubc9 localizes to both the cytoplasmic and the nucleoplasmic filaments of the NPC [15].
  • An antibody that was generated against the bacterially expressed glutathione S-transferase-hUBC9 detected a approximately 19-kDa protein, which localizes predominantly in the nuclei of T cells [16].
  • Immunohistochemistry showed that Ubc9 and PIAS1 are markedly expressed in rat adrenal glomerulosa cells [17].
  • When IR1+2 tagged with green fluorescence protein at its amino terminus (GFP-IR1+2) was transfected into COS-7 cells, we found that approximately 90% of the nuclear Ubc9 was sequestered in the cytoplasm [18].
  • Ubc9, a conjugation enzyme for the ubiquitin-related modifier SUMO, is present predominantly in the nucleus and at the nuclear pore complex [18].

Associations of UBE2I with chemical compounds

  • Two other cyclic AMP-responsive element-binding transcription factors, CREB and ATF1, also showed significant levels of interaction with hUBC9 [16].
  • Ubc9-induced inhibition of diadenosine triphosphate hydrolase activity of the putative tumor suppressor protein Fhit [14].
  • A lysine to arginine mutation abolished MITF (K201R) degradation by hUBC9 in vivo [19].
  • Serine 73, which is located in a region rich in proline, glutamic acid, serine, and threonine (PEST), regulates MITF protein stability, since a serine to alanine mutation prevented hUBC9-mediated MITF (S73A) degradation [19].
  • In this study, we found that although MCF7 cells expressing a Ubc9 dominant-negative mutant (Ubc9-DN) display decreased activity of topo I, these cells are more sensitive to the topo I inhibitor topotecan and other anticancer agents such as VM-26 and cisplatin [20].

Physical interactions of UBE2I


Co-localisations of UBE2I


Regulatory relationships of UBE2I


Other interactions of UBE2I


Analytical, diagnostic and therapeutic context of UBE2I

  • To investigate the functional significance of this interaction, site-directed mutagenesis was used to alter residues in the SUMO binding surface of Ubc9, and the effect of the amino acid substitutions on binding and conjugation to SUMO-1 and target protein RanGAP1 was investigated by isothermal titration calorimetry and biochemical analysis [34].
  • CONCLUSIONS: P18 rearrangement or deletion as detected by Southern blot is a rare event in MCL, but may be associated with blastic morphology [35].
  • Proteins p16, p17, and p18 have been localized within the cell by immunofluorescence methods and appear to be present throughout the kDNA [36].
  • Finally, chromatin immunoprecipitation experiments demonstrated that K-bZIP interacts with and recruits Ubc9 to specific KSHV promoters [37].
  • We have previously shown that suppression of sumoylation by a dominant negative Ubc9 mutant (Ubc9-DN) in the estrogen receptor (ER) positive MCF-7 cells is associated with alterations of tumor cell's response to anticancer drugs as well as tumor growth in a xenograft mouse carcinoma model [38].


  1. Functional Interaction between Human Herpesvirus 6 Immediate-Early 2 Protein and Ubiquitin-Conjugating Enzyme 9 in the Absence of Sumoylation. Tomoiu, A., Gravel, A., Tanguay, R.M., Flamand, L. J. Virol. (2006) [Pubmed]
  2. Evaluation of interactions of human cytomegalovirus immediate-early IE2 regulatory protein with small ubiquitin-like modifiers and their conjugation enzyme Ubc9. Ahn, J.H., Xu, Y., Jang, W.J., Matunis, M.J., Hayward, G.S. J. Virol. (2001) [Pubmed]
  3. Mutations in the p16INK4/MTS1/CDKN2, p15INK4B/MTS2, and p18 genes in primary and metastatic lung cancer. Okamoto, A., Hussain, S.P., Hagiwara, K., Spillare, E.A., Rusin, M.R., Demetrick, D.J., Serrano, M., Hannon, G.J., Shiseki, M., Zariwala, M. Cancer Res. (1995) [Pubmed]
  4. A role for Ubc9 in tumorigenesis. Mo, Y.Y., Yu, Y., Theodosiou, E., Rachel Ee, P.L., Beck, W.T. Oncogene (2005) [Pubmed]
  5. Covalent modification of human immunodeficiency virus type 1 p6 by SUMO-1. Gurer, C., Berthoux, L., Luban, J. J. Virol. (2005) [Pubmed]
  6. Structural basis for E2-mediated SUMO conjugation revealed by a complex between ubiquitin-conjugating enzyme Ubc9 and RanGAP1. Bernier-Villamor, V., Sampson, D.A., Matunis, M.J., Lima, C.D. Cell (2002) [Pubmed]
  7. Multiple activities contribute to Pc2 E3 function. Kagey, M.H., Melhuish, T.A., Powers, S.E., Wotton, D. EMBO J. (2005) [Pubmed]
  8. PIASy mediates SUMO-2 conjugation of Topoisomerase-II on mitotic chromosomes. Azuma, Y., Arnaoutov, A., Anan, T., Dasso, M. EMBO J. (2005) [Pubmed]
  9. Covalent modification of the androgen receptor by small ubiquitin-like modifier 1 (SUMO-1). Poukka, H., Karvonen, U., Janne, O.A., Palvimo, J.J. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  10. Modulation of TEL transcription activity by interaction with the ubiquitin-conjugating enzyme UBC9. Chakrabarti, S.R., Sood, R., Ganguly, S., Bohlander, S., Shen, Z., Nucifora, G. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  11. Induction of anti-gp160 cytotoxic T cells cross-reacting with various V3 loop P18 peptides in human immunodeficiency virus type 1 envelope-immunized individuals. Achour, A., Bex, F., Hermans, P., Burny, A., Zagury, D. J. Virol. (1996) [Pubmed]
  12. 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. Watanabe, T.K., 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. Cytogenet. Cell Genet. (1996) [Pubmed]
  13. Identification of a substrate recognition site on Ubc9. Lin, D., Tatham, M.H., Yu, B., Kim, S., Hay, R.T., Chen, Y. J. Biol. Chem. (2002) [Pubmed]
  14. Ubc9-induced inhibition of diadenosine triphosphate hydrolase activity of the putative tumor suppressor protein Fhit. Golebiowski, F., Szulc, A., Szutowicz, A., Pawelczyk, T. Arch. Biochem. Biophys. (2004) [Pubmed]
  15. Enzymes of the SUMO modification pathway localize to filaments of the nuclear pore complex. Zhang, H., Saitoh, H., Matunis, M.J. Mol. Cell. Biol. (2002) [Pubmed]
  16. 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. Firestein, R., Feuerstein, N. J. Biol. Chem. (1998) [Pubmed]
  17. Ubc9 and Protein Inhibitor of Activated STAT 1 Activate Chicken Ovalbumin Upstream Promoter-Transcription Factor I-mediated Human CYP11B2 Gene Transcription. Kurihara, I., Shibata, H., Kobayashi, S., Suda, N., Ikeda, Y., Yokota, K., Murai, A., Saito, I., Rainey, W.E., Saruta, T. J. Biol. Chem. (2005) [Pubmed]
  18. Perturbation of SUMOlation enzyme Ubc9 by distinct domain within nucleoporin RanBP2/Nup358. Saitoh, H., Pizzi, M.D., Wang, J. J. Biol. Chem. (2002) [Pubmed]
  19. Regulation of microphthalmia-associated transcription factor MITF protein levels by association with the ubiquitin-conjugating enzyme hUBC9. Xu, W., Gong, L., Haddad, M.M., Bischof, O., Campisi, J., Yeh, E.T., Medrano, E.E. Exp. Cell Res. (2000) [Pubmed]
  20. Overexpression of a dominant-negative mutant Ubc9 is associated with increased sensitivity to anticancer drugs. Mo, Y.Y., Yu, Y., Ee, P.L., Beck, W.T. Cancer Res. (2004) [Pubmed]
  21. A Kruppel zinc finger of ZNF 146 interacts with the SUMO-1 conjugating enzyme UBC9 and is sumoylated in vivo. Antoine, K., Prosperi, M.T., Ferbus, D., Boule, C., Goubin, G. Mol. Cell. Biochem. (2005) [Pubmed]
  22. Unique binding interactions among Ubc9, SUMO and RanBP2 reveal a mechanism for SUMO paralog selection. Tatham, M.H., Kim, S., Jaffray, E., Song, J., Chen, Y., Hay, R.T. Nat. Struct. Mol. Biol. (2005) [Pubmed]
  23. Solution structure of human SUMO-3 C47S and its binding surface for Ubc9. Ding, H., Xu, Y., Chen, Q., Dai, H., Tang, Y., Wu, J., Shi, Y. Biochemistry (2005) [Pubmed]
  24. The homeodomain-interacting kinase PKM (HIPK-2) modifies ND10 through both its kinase domain and a SUMO-1 interaction motif and alters the posttranslational modification of PML. Engelhardt, O.G., Boutell, C., Orr, A., Ullrich, E., Haller, O., Everett, R.D. Exp. Cell Res. (2003) [Pubmed]
  25. Ubc9 interacts with SOX4 and represses its transcriptional activity. Pan, X., Li, H., Zhang, P., Jin, B., Man, J., Tian, L., Su, G., Zhao, J., Li, W., Liu, H., Gong, W., Zhou, T., Zhang, X. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  26. Association of FHIT (fragile histidine triad), a candidate tumour suppressor gene, with the ubiquitin-conjugating enzyme hUBC9. Shi, Y., Zou, M., Farid, N.R., Paterson, M.C. Biochem. J. (2000) [Pubmed]
  27. SUMO-1/Ubc9 promotes nuclear accumulation and metabolic stability of tumor suppressor Smad4. Lin, X., Liang, M., Liang, Y.Y., Brunicardi, F.C., Feng, X.H. J. Biol. Chem. (2003) [Pubmed]
  28. Differential modulation of androgen receptor action by deoxyribonucleic acid response elements. Geserick, C., Meyer, H.A., Barbulescu, K., Haendler, B. Mol. Endocrinol. (2003) [Pubmed]
  29. Suppression of ARG kinase activity by STI571 induces cell cycle arrest through up-regulation of CDK inhibitor p18/INK4c. Nishimura, N., Furukawa, Y., Sutheesophon, K., Nakamura, M., Kishi, K., Okuda, K., Sato, Y., Kano, Y. Oncogene (2003) [Pubmed]
  30. SUMO-1 modification activates the transcriptional response of p53. Rodriguez, M.S., Desterro, J.M., Lain, S., Midgley, C.A., Lane, D.P., Hay, R.T. EMBO J. (1999) [Pubmed]
  31. Sterol regulatory element-binding proteins are negatively regulated through SUMO-1 modification independent of the ubiquitin/26 S proteasome pathway. Hirano, Y., Murata, S., Tanaka, K., Shimizu, M., Sato, R. J. Biol. Chem. (2003) [Pubmed]
  32. The DNA topoisomerase I binding protein topors as a novel cellular target for SUMO-1 modification: characterization of domains necessary for subcellular localization and sumolation. Weger, S., Hammer, E., Engstler, M. Exp. Cell Res. (2003) [Pubmed]
  33. Interaction of the developmental regulator SALL1 with UBE2I and SUMO-1. Netzer, C., Bohlander, S.K., Rieger, L., Müller, S., Kohlhase, J. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  34. Role of an N-terminal site of Ubc9 in SUMO-1, -2, and -3 binding and conjugation. Tatham, M.H., Kim, S., Yu, B., Jaffray, E., Song, J., Zheng, J., Rodriguez, M.S., Hay, R.T., Chen, Y. Biochemistry (2003) [Pubmed]
  35. Analysis of the cyclin-dependent kinase inhibitors p18 and p19 in mantle-cell lymphoma and chronic lymphocytic leukemia. Williams, M.E., Whitefield, M., Swerdlow, S.H. Ann. Oncol. (1997) [Pubmed]
  36. Nucleus-encoded histone H1-like proteins are associated with kinetoplast DNA in the trypanosomatid Crithidia fasciculata. Xu, C.W., Hines, J.C., Engel, M.L., Russell, D.G., Ray, D.S. Mol. Cell. Biol. (1996) [Pubmed]
  37. Kaposi's sarcoma-associated herpesvirus K-bZIP represses gene transcription via SUMO modification. Izumiya, Y., Ellison, T.J., Yeh, E.T., Jung, J.U., Luciw, P.A., Kung, H.J. J. Virol. (2005) [Pubmed]
  38. Regulation of bcl-2 expression by Ubc9. Lu, Z., Wu, H., Mo, Y.Y. Exp. Cell Res. (2006) [Pubmed]
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