UBE2L3 explained

Ubiquitin-conjugating enzyme E2 L3 (UBE2L3), also called UBCH7, is a protein that in humans is encoded by the UBE2L3 gene.^{[1] [2] [3]} As an E2 enzyme, UBE2L3 participates in ubiquitination to target proteins for degradation.^[3] The role of UBE2L3 in the ubiquitination of the NF-κB precursor implicated it in various major autoimmune diseases, including rheumatoid arthritis (RA), celiac disease, Crohn's disease (CD), and systemic lupus erythematosus.^[4]

Structure

Gene

The UBE2L3 gene is located at chromosome 22q11.21, consisting of 6 exons. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.^[3]

Protein

There are 38 E2 enzymes in humans.^[5] They all contain a conserved catalytic core domain that interacts with E1 and E3 and many E2s possess additional N- and/or C-terminal protein sequences.^{[6] [7]} In contrast to other E2s, residues necessary for lysine reactivity are absent: the D87 and D117 residues (in UBCH5C numbering) are replaced by Pro and His residues.^[8]

Function

The modification of proteins with ubiquitin is an important cellular mechanism for targeting abnormal or short-lived proteins for degradation. Ubiquitination involves at least three classes of enzymes: ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s) and ubiquitin-protein ligases (E3s). E2s play a key role in the whole ubiquitin (Ub) transfer pathway and are responsible for Ub cellular signaling. Unlike many E2s that transfer Ub with RINGs, UBE2L3 has E3-independent reactivity with lysine.^[8] This enzyme is demonstrated to participate in the ubiquitination of p53, c-Fos, and the NF-κB precursor p105 in vitro. UBE2L3 is primarily known for its role in the cell cycle. Specifically, UBE2L3 manages cell cycle regulatory protein levels via the ubiquitin proteolytic pathway (UPP) during the G1/S transition and during the actual S phase.^[9]

Clinical significance

Through genome-wide association studies (GWAS), UBE2L3 has been associated with several autoimmune diseases, including RA, celiac disease, CD, and SLE via the ubiquitination of the NK-κB precursor.^{[9] [10] [11]} This association was observed in European, Asian, and African-American populations.^[9] UBE2L3 has been linked to natural killer cell cytotoxic function, and high UBE2L3 levels had contributed to clearing chronic HBV infection.^{[4] [11]} UBE2L3 controls the protein stability of 53BP1 and determines the DNA double-strand break repair choice. Loss of UBE2L3 stabilizes 53BP1 and force cells to choose NHEJ to repair DNA double-strand break. Repair by NHEJ leads to radial chromosomes and cell death.^{[12] [13]} UBE2L3 depletion may become a novel strategy in enhancing the effect of anticancer therapies.^[14] The haplotype of UBE2L3 gene is also reported associated with Hashimoto's thyroiditis in a Chinese Han population.^[15] (27094594)

Interactions

UBE2L3 has been shown to interact with:

• ARIH1,^{[16] [17] [18]}
• ARIH2,
• CBL,^{[19] [20] [21]}
• CHEK1,^[22]
• NEDD4,^[23]
• PARK2,^[22]
• SMURF2,^[22]
• TNFAIP3,^[10]
• TNFSF4,^[10]
• TNIP1,^[10]
• TRAF6,^[22]
• UBE3A,^[22]
• UBE3A,^{[24] [25] [26]} and
• UBOX5.^[27]

External links

Further reading

• Blumenfeld N, Gonen H, Mayer A, Smith CE, Siegel NR, Schwartz AL, Ciechanover A . Purification and characterization of a novel species of ubiquitin-carrier protein, E2, that is involved in degradation of non-"N-end rule" protein substrates . J. Biol. Chem. . 269 . 13 . 9574–81 . 1994 . 10.1016/S0021-9258(17)36920-X . 8144544 . free .
• Robinson PA, Leek JP, Thompson J, Carr IM, Bailey A, Moynihan TP, Coletta PL, Lench NJ, Markham AF . A human ubiquitin conjugating enzyme, L-UBC, maps in the Alzheimer's disease locus on chromosome 14q24.3 . Mamm. Genome . 6 . 10 . 725–31 . 1995 . 8563171 . 10.1007/BF00354295 . 9212706 .
• Kumar S, Kao WH, Howley PM . Physical interaction between specific E2 and Hect E3 enzymes determines functional cooperativity . J. Biol. Chem. . 272 . 21 . 13548–54 . 1997 . 9153201 . 10.1074/jbc.272.21.13548 . free .
• Martinez-Noel G, Niedenthal R, Tamura T, Harbers K . A family of structurally related RING finger proteins interacts specifically with the ubiquitin-conjugating enzyme UbcM4 . FEBS Lett. . 454 . 3 . 257–61 . 1999 . 10431818 . 10.1016/S0014-5793(99)00823-6 . 46159115 . free .
• Ardley HC, Moynihan TP, Markham AF, Robinson PA . Promoter analysis of the human ubiquitin-conjugating enzyme gene family UBE2L1-4, including UBE2L3 which encodes UbcH7 . Biochim. Biophys. Acta . 1491 . 1–3 . 57–64 . 2000 . 10760570 . 10.1016/s0167-4781(00)00024-5 .
• Zhang Y, Gao J, Chung KK, Huang H, Dawson VL, Dawson TM . Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1 . Proc. Natl. Acad. Sci. U.S.A. . 97 . 24 . 13354–9 . 2000 . 11078524 . 27228 . 10.1073/pnas.240347797 . 2000PNAS...9713354Z . free .
• Niwa J, Ishigaki S, Doyu M, Suzuki T, Tanaka K, Sobue G . A novel centrosomal ring-finger protein, dorfin, mediates ubiquitin ligase activity . Biochem. Biophys. Res. Commun. . 281 . 3 . 706–13 . 2001 . 11237715 . 10.1006/bbrc.2001.4414 .
• Obin M, Lee BY, Meinke G, Bohm A, Lee RH, Gaudet R, Hopp JA, Arshavsky VY, Willardson BM, Taylor A . Ubiquitylation of the transducin betagamma subunit complex. Regulation by phosducin . J. Biol. Chem. . 277 . 46 . 44566–75 . 2002 . 12215439 . 10.1074/jbc.M205308200 . free .

Notes and References

1. Moynihan TP, Ardley HC, Leek JP, Thompson J, Brindle NS, Markham AF, Robinson PA . Characterization of a human ubiquitin-conjugating enzyme gene UBE2L3 . Mamm. Genome . 7 . 7 . 520–5 . October 1996 . 8672131 . 10.1007/s003359900155 . 36212813 .
2. Moynihan TP, Cole CG, Dunham I, O'Neil L, Markham AF, Robinson PA . Fine-mapping, genomic organization, and transcript analysis of the human ubiquitin-conjugating enzyme gene UBE2L3 . Genomics . 51 . 1 . 124–7 . September 1998 . 9693040 . 10.1006/geno.1998.5257 .
3. Web site: Entrez Gene: UBE2L3 ubiquitin-conjugating enzyme E2L 3.
4. Hu Z, Liu Y, Zhai X, Dai J, Jin G, Wang L, Zhu L, Yang Y, Liu J, Chu M, Wen J, Xie K, Du G, Wang Q, Zhou Y, Cao M, Liu L, He Y, Wang Y, Zhou G, Jia W, Lu J, Li S, Liu J, Yang H, Shi Y, Zhou W, Shen H . 6 . New loci associated with chronic hepatitis B virus infection in Han Chinese . Nature Genetics . 45 . 12 . 1499–503 . Dec 2013 . 24162738 . 10.1038/ng.2809 . 23028494 .
5. Deshaies RJ, Joazeiro CA . RING domain E3 ubiquitin ligases . Annual Review of Biochemistry . 78 . 399–434 . 2009 . 19489725 . 10.1146/annurev.biochem.78.101807.093809 . 35042803 .
6. Eletr ZM, Huang DT, Duda DM, Schulman BA, Kuhlman B . E2 conjugating enzymes must disengage from their E1 enzymes before E3-dependent ubiquitin and ubiquitin-like transfer . Nature Structural & Molecular Biology . 12 . 10 . 933–4 . October 2005 . 16142244 . 10.1038/nsmb984 . 40700043 .
7. Wenzel DM, Stoll KE, Klevit RE . E2s: structurally economical and functionally replete . The Biochemical Journal . 433 . 1 . 31–42 . January 2011 . 21158740 . 10.1042/BJ20100985 . 3118098.
8. Wenzel DM, Lissounov A, Brzovic PS, Klevit RE . UBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT hybrids . Nature . 474 . 7349 . 105–8 . June 2011 . 21532592 . 10.1038/nature09966 . 3444301.
9. Wang S, Adrianto I, Wiley GB, Lessard CJ, Kelly JA, Adler AJ, Glenn SB, Williams AH, Ziegler JT, Comeau ME, Marion MC, Wakeland BE, Liang C, Kaufman KM, Guthridge JM, Alarcón-Riquelme ME, Alarcón GS, Anaya JM, Bae SC, Kim JH, Joo YB, Boackle SA, Brown EE, Petri MA, Ramsey-Goldman R, Reveille JD, Vilá LM, Criswell LA, Edberg JC, Freedman BI, Gilkeson GS, Jacob CO, James JA, Kamen DL, Kimberly RP, Martin J, Merrill JT, Niewold TB, Pons-Estel BA, Scofield RH, Stevens AM, Tsao BP, Vyse TJ, Langefeld CD, Harley JB, Wakeland EK, Moser KL, Montgomery CG, Gaffney PM . 6 . A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus . Genes and Immunity . 13 . 5 . 380–7 . Jul 2012 . 22476155 . 10.1038/gene.2012.6 . 3411915.
10. Zuo XB, Sheng YJ, Hu SJ, Gao JP, Li Y, Tang HY, Tang XF, Cheng H, Yin XY, Wen LL, Sun LD, Yang S, Cui Y, Zhang XJ. Variants in TNFSF4, TNFAIP3, TNIP1, BLK, SLC15A4 and UBE2L3 interact to confer risk of systemic lupus erythematosus in Chinese population. Rheumatol Int. 34. 459–64. 24091983 . 10.1007/s00296-013-2864-3 . 2014 . 4. 22804352.
11. Fransen K, Visschedijk MC, van Sommeren S, Fu JY, Franke L, Festen EA, Stokkers PC, van Bodegraven AA, Crusius JB, Hommes DW, Zanen P, de Jong DJ, Wijmenga C, van Diemen CC, Weersma RK . Analysis of SNPs with an effect on gene expression identifies UBE2L3 and BCL3 as potential new risk genes for Crohn's disease . Human Molecular Genetics . 19 . 17 . 3482–8 . September 2010 . 20601676 . 10.1093/hmg/ddq264 . free .
12. Bouwman P, Aly A, Escandell JM, Pieterse M, Bartkova J, van der Gulden H, Hiddingh S, Thanasoula M, Kulkarni A, Yang Q, Haffty BG, Tommiska J, Blomqvist C, Drapkin R, Adams DJ, Nevanlinna H, Bartek J, Tarsounas M, Ganesan S, Jonkers J . 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers . Nature Structural & Molecular Biology . 17 . 6 . 688–95 . June 2010 . 20453858 . 10.1038/nsmb.1831 . 2912507.
13. Cao L, Xu X, Bunting SF, Liu J, Wang RH, Cao LL, Wu JJ, Peng TN, Chen J, Nussenzweig A, Deng CX, Finkel T . A selective requirement for 53BP1 in the biological response to genomic instability induced by Brca1 deficiency . Molecular Cell . 35 . 4 . 534–41 . August 2009 . 19716796 . 10.1016/j.molcel.2009.06.037 . 3392030.
14. Mitchell LJ, Moody CJ . Solar photochemical oxidation of alcohols using catalytic hydroquinone and copper nanoparticles under oxygen: oxidative cleavage of lignin models . The Journal of Organic Chemistry . 79 . 22 . 11091–100 . November 2014 . 25322456 . 10.1021/jo5020917 .
15. Wang Y, Zhu YF, Wang Q, Xu J, Yan N, Xu J, Shi LF, He ST, Zhang JA . The haplotype of UBE2L3 gene is associated with Hashimoto's thyroiditis in a Chinese Han population . BMC Endocrine Disorders . 16 . 18 . 19 April 2016 . 27094594 . 10.1186/s12902-016-0098-6 . 4837539 . free .
16. Tan NG, Ardley HC, Scott GB, Rose SA, Markham AF, Robinson PA . Human homologue of ariadne promotes the ubiquitylation of translation initiation factor 4E homologous protein, 4EHP . FEBS Lett. . 554 . 3 . 501–4 . November 2003 . 14623119 . 10.1016/s0014-5793(03)01235-3. free .
17. Moynihan TP, Ardley HC, Nuber U, Rose SA, Jones PF, Markham AF, Scheffner M, Robinson PA . The ubiquitin-conjugating enzymes UbcH7 and UbcH8 interact with RING finger/IBR motif-containing domains of HHARI and H7-AP1 . J. Biol. Chem. . 274 . 43 . 30963–8 . October 1999 . 10521492 . 10.1074/jbc.274.43.30963. free .
18. Ardley HC, Tan NG, Rose SA, Markham AF, Robinson PA . Features of the parkin/ariadne-like ubiquitin ligase, HHARI, that regulate its interaction with the ubiquitin-conjugating enzyme, Ubch7 . J. Biol. Chem. . 276 . 22 . 19640–7 . June 2001 . 11278816 . 10.1074/jbc.M011028200 . free .
19. Yokouchi M, Kondo T, Houghton A, Bartkiewicz M, Horne WC, Zhang H, Yoshimura A, Baron R . Ligand-induced ubiquitination of the epidermal growth factor receptor involves the interaction of the c-Cbl RING finger and UbcH7 . J. Biol. Chem. . 274 . 44 . 31707–12 . October 1999 . 10531381 . 10.1074/jbc.274.44.31707. free .
20. Zheng N, Wang P, Jeffrey PD, Pavletich NP . Structure of a c-Cbl-UbcH7 complex: RING domain function in ubiquitin-protein ligases . Cell . 102 . 4 . 533–9 . August 2000 . 10966114 . 10.1016/S0092-8674(00)00057-X. free .
21. Wong ES, Fong CW, Lim J, Yusoff P, Low BC, Langdon WY, Guy GR . Sprouty2 attenuates epidermal growth factor receptor ubiquitylation and endocytosis, and consequently enhances Ras/ERK signalling . EMBO J. . 21 . 18 . 4796–808 . September 2002 . 12234920 . 126289 . 10.1093/emboj/cdf493.
22. Whitcomb EA, Dudek EJ, Liu Q, Taylor A . Novel control of S phase of the cell cycle by ubiquitin-conjugating enzyme H7 . Molecular Biology of the Cell . 20 . 1 . 1–9 . Jan 2009 . 18946090 . 10.1091/mbc.E08-01-0036 . 2613108.
23. Bruce MC, Kanelis V, Fouladkou F, Debonneville A, Staub O, Rotin D . Regulation of Nedd4-2 self-ubiquitination and stability by a PY motif located within its HECT-domain . Biochem. J. . 415 . 1 . 155–63 . October 2008 . 18498246 . 10.1042/BJ20071708 .
24. Anan T, Nagata Y, Koga H, Honda Y, Yabuki N, Miyamoto C, Kuwano A, Matsuda I, Endo F, Saya H, Nakao M . Human ubiquitin-protein ligase Nedd4: expression, subcellular localization and selective interaction with ubiquitin-conjugating enzymes . Genes Cells . 3 . 11 . 751–63 . November 1998 . 9990509 . 10.1046/j.1365-2443.1998.00227.x. 1653536 .
25. Nuber U, Schwarz S, Kaiser P, Schneider R, Scheffner M . Cloning of human ubiquitin-conjugating enzymes UbcH6 and UbcH7 (E2-F1) and characterization of their interaction with E6-AP and RSP5 . J. Biol. Chem. . 271 . 5 . 2795–800 . February 1996 . 8576257 . 10.1074/jbc.271.5.2795. free .
26. Huang L, Kinnucan E, Wang G, Beaudenon S, Howley PM, Huibregtse JM, Pavletich NP . Structure of an E6AP-UbcH7 complex: insights into ubiquitination by the E2-E3 enzyme cascade . Science . 286 . 5443 . 1321–6 . November 1999 . 10558980 . 10.1126/science.286.5443.1321.
27. Pringa E, Martinez-Noel G, Muller U, Harbers K . Interaction of the ring finger-related U-box motif of a nuclear dot protein with ubiquitin-conjugating enzymes . J. Biol. Chem. . 276 . 22 . 19617–23 . June 2001 . 11274149 . 10.1074/jbc.M100192200 . free .