Ubiquitin-conjugating enzyme E2 L3 (UBE2L3), also called UBCH7, is a protein that in humans is encoded by the UBE2L3 gene.[5][6][7] As an E2 enzyme, UBE2L3 participates in ubiquitination to target proteins for degradation.[7] 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.[8]
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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.[7]
Protein
There are 38 E2 enzymes in humans.[9] 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.[10][11] 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.[12]
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.[12] 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.[13]
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.[13][14][15] This association was observed in European, Asian, and African-American populations.[13] UBE2L3 has been linked to natural killer cell cytotoxic function, and high UBE2L3 levels had contributed to clearing chronic HBV infection.[8][15] 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.[16][17] UBE2L3 depletion may become a novel strategy in enhancing the effect of anticancer therapies.[18] The haplotype of UBE2L3 gene is also reported associated with Hashimoto's thyroiditis in a Chinese Han population.[19](27094594)
UBE2L3 has been shown to interact with:
- ARIH1,[20][21][22]
- ARIH2,[23]
- CBL,[24][25][26]
- CHEK1,[23]
- NEDD4,[27][28]
- PARK2,[23]
- SMURF2,[23]
- TNFAIP3,[14]
- TNFSF4,[14]
- TNIP1,[14]
- TRAF6,[23]
- UBE3A,[23]
- UBE3A,[27][29][30] and
- UBOX5.[31]
Moynihan TP, Ardley HC, Leek JP, Thompson J, Brindle NS, Markham AF, Robinson PA (October 1996). "Characterization of a human ubiquitin-conjugating enzyme gene UBE2L3". Mamm. Genome. 7 (7): 520–5. doi:10.1007/s003359900155. PMID 8672131. S2CID 36212813.
Moynihan TP, Cole CG, Dunham I, O'Neil L, Markham AF, Robinson PA (September 1998). "Fine-mapping, genomic organization, and transcript analysis of the human ubiquitin-conjugating enzyme gene UBE2L3". Genomics. 51 (1): 124–7. doi:10.1006/geno.1998.5257. PMID 9693040.
Hu Z, Liu Y, Zhai X, Dai J, Jin G, Wang L, et al. (Dec 2013). "New loci associated with chronic hepatitis B virus infection in Han Chinese". Nature Genetics. 45 (12): 1499–503. doi:10.1038/ng.2809. PMID 24162738. S2CID 23028494.
Eletr ZM, Huang DT, Duda DM, Schulman BA, Kuhlman B (October 2005). "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. doi:10.1038/nsmb984. PMID 16142244. S2CID 40700043.
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 (2014). "Variants in TNFSF4, TNFAIP3, TNIP1, BLK, SLC15A4 and UBE2L3 interact to confer risk of systemic lupus erythematosus in Chinese population". Rheumatol Int. 34 (4): 459–64. doi:10.1007/s00296-013-2864-3. PMID 24091983. S2CID 22804352.
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 (September 2010). "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. doi:10.1093/hmg/ddq264. PMID 20601676.
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 (June 2010). "53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers". Nature Structural & Molecular Biology. 17 (6): 688–95. doi:10.1038/nsmb.1831. PMC 2912507. PMID 20453858.
Cao L, Xu X, Bunting SF, Liu J, Wang RH, Cao LL, Wu JJ, Peng TN, Chen J, Nussenzweig A, Deng CX, Finkel T (August 2009). "A selective requirement for 53BP1 in the biological response to genomic instability induced by Brca1 deficiency". Molecular Cell. 35 (4): 534–41. doi:10.1016/j.molcel.2009.06.037. PMC 3392030. PMID 19716796.
Mitchell LJ, Moody CJ (November 2014). "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. doi:10.1021/jo5020917. PMID 25322456.
Anan T, Nagata Y, Koga H, Honda Y, Yabuki N, Miyamoto C, Kuwano A, Matsuda I, Endo F, Saya H, Nakao M (November 1998). "Human ubiquitin-protein ligase Nedd4: expression, subcellular localization and selective interaction with ubiquitin-conjugating enzymes". Genes Cells. 3 (11): 751–63. doi:10.1046/j.1365-2443.1998.00227.x. PMID 9990509. S2CID 1653536.
Bruce MC, Kanelis V, Fouladkou F, Debonneville A, Staub O, Rotin D (October 2008). "Regulation of Nedd4-2 self-ubiquitination and stability by a PY motif located within its HECT-domain". Biochem. J. 415 (1): 155–63. doi:10.1042/BJ20071708. PMID 18498246.
Huang L, Kinnucan E, Wang G, Beaudenon S, Howley PM, Huibregtse JM, Pavletich NP (November 1999). "Structure of an E6AP-UbcH7 complex: insights into ubiquitination by the E2-E3 enzyme cascade". Science. 286 (5443): 1321–6. doi:10.1126/science.286.5443.1321. PMID 10558980.
- Overview of all the structural information available in the PDB for UniProt: P68036 (Ubiquitin-conjugating enzyme E2 L3) at the PDBe-KB.
- Blumenfeld N, Gonen H, Mayer A, Smith CE, Siegel NR, Schwartz AL, Ciechanover A (1994). "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. doi:10.1016/S0021-9258(17)36920-X. PMID 8144544.
- Robinson PA, Leek JP, Thompson J, Carr IM, Bailey A, Moynihan TP, Coletta PL, Lench NJ, Markham AF (1995). "A human ubiquitin conjugating enzyme, L-UBC, maps in the Alzheimer's disease locus on chromosome 14q24.3". Mamm. Genome. 6 (10): 725–31. doi:10.1007/BF00354295. PMID 8563171. S2CID 9212706.
- Kumar S, Kao WH, Howley PM (1997). "Physical interaction between specific E2 and Hect E3 enzymes determines functional cooperativity". J. Biol. Chem. 272 (21): 13548–54. doi:10.1074/jbc.272.21.13548. PMID 9153201.
- Martinez-Noel G, Niedenthal R, Tamura T, Harbers K (1999). "A family of structurally related RING finger proteins interacts specifically with the ubiquitin-conjugating enzyme UbcM4". FEBS Lett. 454 (3): 257–61. doi:10.1016/S0014-5793(99)00823-6. PMID 10431818. S2CID 46159115.
- Ardley HC, Moynihan TP, Markham AF, Robinson PA (2000). "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. doi:10.1016/s0167-4781(00)00024-5. PMID 10760570.
- Zhang Y, Gao J, Chung KK, Huang H, Dawson VL, Dawson TM (2000). "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. Bibcode:2000PNAS...9713354Z. doi:10.1073/pnas.240347797. PMC 27228. PMID 11078524.
- Niwa J, Ishigaki S, Doyu M, Suzuki T, Tanaka K, Sobue G (2001). "A novel centrosomal ring-finger protein, dorfin, mediates ubiquitin ligase activity". Biochem. Biophys. Res. Commun. 281 (3): 706–13. doi:10.1006/bbrc.2001.4414. PMID 11237715.
- Obin M, Lee BY, Meinke G, Bohm A, Lee RH, Gaudet R, Hopp JA, Arshavsky VY, Willardson BM, Taylor A (2002). "Ubiquitylation of the transducin betagamma subunit complex. Regulation by phosducin". J. Biol. Chem. 277 (46): 44566–75. doi:10.1074/jbc.M205308200. PMID 12215439.