UBE2D3

Summary

UBE2D3 (ubiquitin conjugating enzyme E2 D3, HGNC:12476) is a protein-coding gene on chromosome 4q24, encoding Ubiquitin-conjugating enzyme E2 D3 (P61077). Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. It is a selective cancer dependency (DepMap: 75.1% of cell lines).

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, or E1s, ubiquitin-conjugating enzymes, or E2s, and ubiquitin-protein ligases, or E3s. This gene encodes a member of the E2 ubiquitin-conjugating enzyme family. This enzyme functions in the ubiquitination of the tumor-suppressor protein p53, which is induced by an E3 ubiquitin-protein ligase.

Source: NCBI Gene 7323 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 30 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 75.1% of screened cell lines
• MANE Select transcript: NM_181891

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12476
Approved symbol	UBE2D3
Name	ubiquitin conjugating enzyme E2 D3
Location	4q24
Locus type	gene with protein product
Status	Approved
Aliases	UbcH5C
Ensembl gene	ENSG00000109332
Ensembl biotype	protein_coding
OMIM	602963
Entrez	7323

Gene structure

Transcript identifiers

Ensembl transcripts: 76 — 62 protein_coding, 7 nonsense_mediated_decay, 6 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000321805, ENST00000338145, ENST00000343106, ENST00000349311, ENST00000350435, ENST00000357194, ENST00000394801, ENST00000394803, ENST00000394804, ENST00000453744, ENST00000502404, ENST00000502563, ENST00000502690, ENST00000503282, ENST00000503418, ENST00000503742, ENST00000504211, ENST00000505009, ENST00000505207, ENST00000505307, ENST00000507845, ENST00000508238, ENST00000508249, ENST00000508474, ENST00000508476, ENST00000508635, ENST00000508818, ENST00000508974, ENST00000510129, ENST00000510599, ENST00000513098, ENST00000514755, ENST00000618836, ENST00000895034, ENST00000895035, ENST00000895036, ENST00000895037, ENST00000895038, ENST00000895039, ENST00000895040, ENST00000895041, ENST00000895042, ENST00000895043, ENST00000895044, ENST00000895046, ENST00000895048, ENST00000895049, ENST00000895050, ENST00000895051, ENST00000895052, ENST00000895053, ENST00000895054, ENST00000895055, ENST00000895056, ENST00000895057, ENST00000895058, ENST00000895059, ENST00000895060, ENST00000895061, ENST00000895062, ENST00000895063, ENST00000917675, ENST00000917676, ENST00000917677, ENST00000917678, ENST00000917679, ENST00000917680, ENST00000917681, ENST00000917682, ENST00000917683, ENST00000917684, ENST00000917685, ENST00000917686, ENST00000917687, ENST00000941277, ENST00000941278

RefSeq mRNA: 10 — MANE Select: NM_181891 NM_001300795, NM_003340, NM_181886, NM_181887, NM_181888, NM_181889, NM_181890, NM_181891, NM_181892, NM_181893

CCDS: CCDS3659, CCDS3660, CCDS3661, CCDS75172

Canonical transcript exons

ENST00000453744 — 8 exons

Exon	Start	End
ENSE00001519638	102827427	102827551
ENSE00002054015	102794383	102797460
ENSE00003470594	102799407	102799500
ENSE00003638329	102826485	102826636
ENSE00003649412	102809672	102809703
ENSE00003669021	102809792	102809855
ENSE00003674735	102802561	102802638
ENSE00003789152	102801454	102801559

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 261.8401 / max 2746.9586, expressed in 1828 samples.

FANTOM5 promoters (29 alternative TSS)

Promoter ID	TPM avg	Samples expressed
53418	62.0468	1825
53417	56.5140	1819
53420	34.5706	1815
53410	26.7385	1813
53421	17.1499	1806
53409	14.1635	1742
53415	10.7891	1744
53423	6.3648	1674
53419	4.0305	1495
53416	3.7511	1518

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.84	gold quality
oocyte	CL:0000023	99.60	gold quality
sperm	CL:0000019	99.56	gold quality
calcaneal tendon	UBERON:0003701	99.39	gold quality
male germ cell	CL:0000015	99.30	gold quality
monocyte	CL:0000576	99.25	gold quality
mononuclear cell	CL:0000842	99.25	gold quality
leukocyte	CL:0000738	99.24	gold quality
adrenal tissue	UBERON:0018303	99.23	gold quality
tendon	UBERON:0000043	99.21	gold quality
buccal mucosa cell	CL:0002336	99.20	gold quality
blood	UBERON:0000178	99.15	gold quality
cartilage tissue	UBERON:0002418	99.08	gold quality
islet of Langerhans	UBERON:0000006	98.99	gold quality
vermiform appendix	UBERON:0001154	98.97	gold quality
right lung	UBERON:0002167	98.96	gold quality
amniotic fluid	UBERON:0000173	98.95	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	98.93	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.93	gold quality
colonic mucosa	UBERON:0000317	98.90	gold quality
bone marrow cell	CL:0002092	98.89	gold quality
caecum	UBERON:0001153	98.89	gold quality
jejunal mucosa	UBERON:0000399	98.88	gold quality
right adrenal gland	UBERON:0001233	98.88	gold quality
left adrenal gland	UBERON:0001234	98.88	gold quality
right adrenal gland cortex	UBERON:0035827	98.88	gold quality
lymph node	UBERON:0000029	98.87	gold quality
superficial temporal artery	UBERON:0001614	98.87	gold quality
endometrium	UBERON:0001295	98.85	gold quality
peritoneum	UBERON:0002358	98.85	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-6505	yes	2031.19
E-HCAD-4	yes	48.15
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, CTBP1, DLX4, GRHL3, HDAC1, SNAI2

miRNA regulators (miRDB)

210 targeting UBE2D3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 75.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 21)

• Transducin beta-gamma is a substrate of UbcH5c (UBE2D3), UbcH7 (UBE2L3) and the ubiquitin-proteasome pathway only following the dissociation of transducin alpha from beta-gamma. Transducin beta-gamma is protected from ubiquitylation by phosducin. (PMID:12215439)
• UbcH5B/C are E2s for Mdm2, which contribute to the maintenance of low levels of p53 and Mdm2 in unstressed cells; inhibition of p53 ubiquitination and degradation by targeting UbcH5B/C is not sufficient to up-regulate p53 transcriptional activity. (PMID:15280377)
• Knocking down UBE2D3 by RNA interference leads to blockage oof retinoic acid induced chclin D1 degradation and cell cycle arrest. (PMID:17420285)
• These results suggest that UbcH5 regulates ZIPK accumulation in PML-NBs by interacting with ZIPK and stimulating its ubiquitination. (PMID:18515077)
• role of WW3 and WW4 domains of Nedd4-2 in dopamine transporter ubiquitination was demonstrated; siRNA analysis demonstrated that this polyubiquitination is mediated by Nedd4-2 cooperation with UBE2D and UBE2L3 E2 ubiquitin-conjugating enzymes (PMID:20051513)
• Combined Actions of UbcH5c and Cdc34 Promote Rapid and Efficient Polyubiquitination of IkBa (PMID:20347421)
• determined structures of E4B U box free and bound to UbcH5c and Ubc4 E2s; findings show E4B U box is a monomer stabilized by a network of hydrogen bonds; findings suggest allosteric regulation of UbcH5c and Ubc4 by E4B U box (PMID:20696396)
• UbcH5c approximately Ub conjugate populates an array of extended conformations, and the population of Ubc13 approximately Ub conjugates favors a closed conformation in which the hydrophobic surface of Ub faces helix 2 of Ubc13 (PMID:21226485)
• The crystal structure of a complex of the Bmi1/Ring1b RING-RING heterodimer & UbcH5c shows that UbcH5c interacts with Ring1b only. (PMID:21772249)
• although a reduction in interdomain dynamics of UbcH5c~Ub is observed upon binding to E4B, Ub retains an extensive degree of flexibility (PMID:23550736)
• UBE2D3 participates in the process of radiosensitivity in human breast cancer cells by regulating TERT and cyclin D1. (PMID:23741361)
• This study demonistrated by Gene expression profile that UBE3D3 upregulaion in fibroblasts of Huntington’s disease patients. (PMID:24296361)
• These data reveal novel insights into the Otub1 inhibition of E2 wherein monoubiquitination promotes the interaction of Otub1 with UbcH5 and the function to suppress it. (PMID:24403071)
• UbcH5c~Ubiqitin binding stabilizes an active conformation of the Shigella flexneri OspG kinase, greatly enhancing its activity. (PMID:24446487)
• Data show that ubiquitin E2 enzymes UBE2D1/2/3 and E3 ligase RNF138 accumulate at DNA-damage sites and act at early resection stages by promoting CtIP protein ubiquitylation and accrual. (PMID:26502057)
• Findings indicate that UBE2D3 enhances radiosensitivity of EC109 cells by degradating hTERT through the ubiquitin proteolysis pathway. (PMID:27105523)
• Together with Riplet, Ube2D3 promotes covalent conjugation of polyubiquitin chains to RIG-I, while Ube2N preferentially facilitates production of unanchored chains. In the presence of these chains, RIG-I induces MAVS aggregation directly on the mitochondria. Data thus reveal two essential mechanisms underlying the activation of RIG-I and MAVS for triggering innate immune signaling in response to viral infection in cells. (PMID:28469175)
• Evolution of an Amniote-Specific Mechanism for Modulating Ubiquitin Signaling via Phosphoregulation of the E2 Enzyme UBE2D3. (PMID:32145025)
• UbcH5 Interacts with Substrates to Participate in Lysine Selection with the E3 Ubiquitin Ligase CHIP. (PMID:32401531)
• UBCH5 Family Members Differentially Impact Stabilization of Mutant p53 via RNF128 Iso1 During Barrett’s Progression to Esophageal Adenocarcinoma. (PMID:34416429)
• Ubiquitinome Profiling Reveals in Vivo UBE2D3 Targets and Implicates UBE2D3 in Protein Quality Control. (PMID:37059365)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ube2d3	ENSDARG00000038473
danio_rerio	ube2d2l	ENSDARG00000099749
mus_musculus	Ube2d3	ENSMUSG00000078578
rattus_norvegicus	Ube2d2	ENSRNOG00000013741

Paralogs (12): UBE2D1 (ENSG00000072401), UBE2D4 (ENSG00000078967), UBE2D2 (ENSG00000131508), UBE2Q2 (ENSG00000140367), UBE2L6 (ENSG00000156587), UBE2Q1 (ENSG00000160714), UBE2E3 (ENSG00000170035), UBE2E1 (ENSG00000170142), UBE2E2 (ENSG00000182247), UBE2L3 (ENSG00000185651), UBE2QL1 (ENSG00000215218), UBE2L5 (ENSG00000236444)

Protein

Protein identifiers

Ubiquitin-conjugating enzyme E2 D3 — P61077 (reviewed: P61077)

Alternative names: (E3-independent) E2 ubiquitin-conjugating enzyme D3, E2 ubiquitin-conjugating enzyme D3, Ubiquitin carrier protein D3, Ubiquitin-conjugating enzyme E2(17)KB 3, Ubiquitin-conjugating enzyme E2-17 kDa 3, Ubiquitin-protein ligase D3

All UniProt accessions (12): P61077, A0A087WY85, D6R933, D6R980, D6R9F6, D6RA11, D6RAH7, D6RAW0, D6RGD0, D6RIZ3, D6RJB3, H9KV45

UniProt curated annotations — full annotation on UniProt →

Function. Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes ‘Lys-11’-, as well as ‘Lys-48’-linked polyubiquitination. Cooperates with the E2 CDC34 and the SCF(FBXW11) E3 ligase complex for the polyubiquitination of NFKBIA leading to its subsequent proteasomal degradation. Acts as an initiator E2, priming the phosphorylated NFKBIA target at positions ‘Lys-21’ and/or ‘Lys-22’ with a monoubiquitin. Ubiquitin chain elongation is then performed by CDC34, building ubiquitin chains from the UBE2D3-primed NFKBIA-linked ubiquitin. Also acts as an initiator E2, in conjunction with RNF8, for the priming of PCNA. Monoubiquitination of PCNA, and its subsequent polyubiquitination, are essential events in the operation of the DNA damage tolerance (DDT) pathway that is activated after DNA damage caused by UV or chemical agents during S-phase. Associates with the BRCA1/BARD1 E3 ligase complex to perform ubiquitination at DNA damage sites following ionizing radiation leading to DNA repair. Targets DAPK3 for ubiquitination which influences promyelocytic leukemia protein nuclear body (PML-NB) formation in the nucleus. In conjunction with the MDM2 and TOPORS E3 ligases, functions ubiquitination of p53/TP53. In conjunction with the CBL E3 ligase, targets EGFR for polyubiquitination at the plasma membrane as well as during its internalization and transport on endosomes. In conjunction with the STUB1 E3 quality control E3 ligase, ubiquitinates unfolded proteins to catalyze their immediate destruction. Together with RNF135, catalyzes the viral RNA-dependent ‘Lys-63’-linked polyubiquitination of RIGI to activate the downstream signaling pathway that leads to interferon beta production. Together with ZNF598, catalyzes ubiquitination of 40S ribosomal proteins in response to ribosome collisions. In cooperation with the GATOR2 complex, catalyzes ‘Lys-6’-linked ubiquitination of NPRL2.

Subunit / interactions. Interacts with SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complex; when Cullin is neddylated, the interaction between the E2 and the SCF complex is strengthened. Interacts with DAPK3. Interacts with BRCA1; the DNA damage checkpoint promotes the association with BRCA1 after ionizing radiation. Interacts non-covalently with ubiquitin. Interacts with E3 ubiquitin-protein ligase CBLC. Interacts with UBTD1. Interacts with RIGI and RNF135; involved in RIGI ubiquitination and activation.

Subcellular location. Cell membrane. Endosome membrane.

Post-translational modifications. Phosphorylated by AURKB.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the ubiquitin-conjugating enzyme family.

Isoforms (3)

UniProt ID	Names	Canonical?
P61077-1	1	yes
P61077-2	2
P61077-3	3

RefSeq proteins (10): NP_001287724, NP_003331, NP_871615, NP_871616, NP_871617, NP_871618, NP_871619, NP_871620, NP_871621, NP_871622 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000608	UBC	Domain
IPR016135	UBQ-conjugating_enzyme/RWD	Homologous_superfamily
IPR023313	UBQ-conjugating_AS	Active_site

Pfam: PF00179

Enzyme classification (BRENDA):

• EC 2.3.2.23 — E2 ubiquitin-conjugating enzyme (BRENDA: 20 organisms, 93 substrates, 28 inhibitors, 12 Km, 8 kcat entries)
• EC 2.3.2.24 — (E3-independent) E2 ubiquitin-conjugating enzyme (BRENDA: 5 organisms, 56 substrates, 7 inhibitors, 6 Km, 6 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
[UBIQUITIN-CARRIER-PROTEIN UBC2B]-L-CYSTEINE	0.0001	5
[UBE2W]-S-UBIQUITINYL-L-CYSTEINE	0.2203–0.3014	2
[HISTONE H2A]-L-LYSINE	0.0008–0.0028	2
[HISTONE H2B]-L-LYSINE	0.0015–0.012	2
S-UBIQUITINYL-[E1 UBIQUITIN-ACTIVATING ENZYME]-L	1	1
[UBIQUITIN CARRIER PROTEIN UBC4]-L-CYSTEINE	0.0019	1
[CYTOCHROME C]-L-LYSINE	0.125	1
[HISTONE H3]-L-LYSINE	0.0013	1

UniProt features (33 total): strand 9, mutagenesis site 6, helix 5, sequence conflict 4, turn 3, splice variant 2, chain 1, domain 1, active site 1, disulfide bond 1

Structure

Experimental structures (PDB)

45 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5EGG	X-RAY DIFFRACTION	1.76
1X23	X-RAY DIFFRACTION	1.85
4S3O	X-RAY DIFFRACTION	2
8UQA	X-RAY DIFFRACTION	2.05
5IFR	X-RAY DIFFRACTION	2.2
8UQ9	X-RAY DIFFRACTION	2.3
8UQ8	X-RAY DIFFRACTION	2.34
3UGB	X-RAY DIFFRACTION	2.35
8AMS	X-RAY DIFFRACTION	2.4
8UQB	X-RAY DIFFRACTION	2.48
6T7F	X-RAY DIFFRACTION	2.58
8UQC	X-RAY DIFFRACTION	2.61
3RPG	X-RAY DIFFRACTION	2.65
4BVU	X-RAY DIFFRACTION	2.7
6CP0	X-RAY DIFFRACTION	3.01
9LPK	ELECTRON MICROSCOPY	3.03
3L1Z	X-RAY DIFFRACTION	3.17
8SMX	ELECTRON MICROSCOPY	3.2
8SMY	ELECTRON MICROSCOPY	3.2
8SMZ	ELECTRON MICROSCOPY	3.2
8SN0	ELECTRON MICROSCOPY	3.2
8UPF	ELECTRON MICROSCOPY	3.2
8X7I	ELECTRON MICROSCOPY	3.27
8X7K	ELECTRON MICROSCOPY	3.27
7LYB	ELECTRON MICROSCOPY	3.28
4R8P	X-RAY DIFFRACTION	3.28
8SMW	ELECTRON MICROSCOPY	3.3
8SN1	ELECTRON MICROSCOPY	3.3
8X7J	ELECTRON MICROSCOPY	3.39
8UQE	X-RAY DIFFRACTION	3.56

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P61077-F1	96.53	0.97

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 85 (glycyl thioester intermediate)

Disulfide bonds (1): 21–107

Mutagenesis-validated functional residues (6):

Position	Phenotype
87	does not affect lysine reactivity.
117	strongly impairs lysine reactivity but retains some ability to transfer ubiquitin to brca1.
77	activity is restricted hect-type and not ring-containing e3 ubiquitin-protein ligases. exhibits ubiquitin transfer with
85	loss of function.
87	has intermediate lysine reactivity.
87	abolishes affect lysine reactivity.

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-1234176	Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha
R-HSA-168927	TICAM1, RIP1-mediated IKK complex recruitment
R-HSA-201451	Signaling by BMP
R-HSA-2173795	Downregulation of SMAD2/3:SMAD4 transcriptional activity
R-HSA-5205685	PINK1-PRKN Mediated Mitophagy
R-HSA-5357905	Regulation of TNFR1 signaling
R-HSA-8866654	E3 ubiquitin ligases ubiquitinate target proteins
R-HSA-8951664	Neddylation
R-HSA-9033241	Peroxisomal protein import
R-HSA-936440	Negative regulators of DDX58/IFIH1 signaling
R-HSA-937041	IKK complex recruitment mediated by RIP1
R-HSA-9705462	Inactivation of CSF3 (G-CSF) signaling
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-9954716	ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA

MSigDB gene sets: 479 (showing top): REACTOME_DDX58_IFIH1_MEDIATED_INDUCTION_OF_INTERFERON_ALPHA_BETA, REACTOME_IKK_COMPLEX_RECRUITMENT_MEDIATED_BY_RIP1, CREL_01, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, LIANG_HEMATOPOIESIS_STEM_CELL_NUMBER_SMALL_VS_HUGE_UP, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, chr4q24, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, ENK_UV_RESPONSE_KERATINOCYTE_UP, GCANCTGNY_MYOD_Q6

GO Biological Process (16): negative regulation of transcription by RNA polymerase II (GO:0000122), protein polyubiquitination (GO:0000209), DNA repair (GO:0006281), ubiquitin-dependent protein catabolic process (GO:0006511), protein monoubiquitination (GO:0006513), apoptotic process (GO:0006915), protein ubiquitination (GO:0016567), negative regulation of BMP signaling pathway (GO:0030514), protein modification process (GO:0036211), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), protein autoubiquitination (GO:0051865), protein K48-linked ubiquitination (GO:0070936), protein K11-linked ubiquitination (GO:0070979), protein K6-linked ubiquitination (GO:0085020), obsolete positive regulation of protein targeting to mitochondrion (GO:1903955), DNA damage response (GO:0006974)

GO Molecular Function (7): ubiquitin-protein transferase activity (GO:0004842), ATP binding (GO:0005524), ubiquitin protein ligase activity (GO:0061630), ubiquitin conjugating enzyme activity (GO:0061631), nucleotide binding (GO:0000166), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (8): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), plasma membrane (GO:0005886), endosome membrane (GO:0010008), extracellular exosome (GO:0070062), endosome (GO:0005768), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Cellular response to hypoxia	1
Toll Like Receptor 3 (TLR3) Cascade	1
Signaling by TGFB family members	1
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	1
Mitophagy	1
TNF signaling	1
Protein ubiquitination	1
Post-translational protein modification	1
Protein localization	1
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1
TRIF (TICAM1)-mediated TLR4 signaling	1
Signaling by CSF3 (G-CSF)	1
Class I MHC mediated antigen processing & presentation	1
Ribosome-associated quality control	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein ubiquitination	4
protein polyubiquitination	3
cellular anatomical structure	3
ubiquitin-protein transferase activity	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
DNA metabolic process	1
DNA damage response	1
modification-dependent protein catabolic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
protein modification by small protein conjugation	1
BMP signaling pathway	1
regulation of BMP signaling pathway	1
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
negative regulation of cellular response to growth factor stimulus	1
protein metabolic process	1
macromolecule modification	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
cellular response to stress	1
ubiquitin-like protein transferase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ubiquitin-like protein ligase activity	1
ubiquitin-like protein conjugating enzyme activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
membrane	1
cell periphery	1
endosome	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

242 interactions, top by confidence:

A	B	Type	Score
UBE2D3	OTUB1	psi-mi:“MI:0915”(physical association)	0.870
OTUB1	UBE2D3	psi-mi:“MI:0915”(physical association)	0.870
RNF25	UBE2D3	psi-mi:“MI:0915”(physical association)	0.850
UBE2D3	RNF25	psi-mi:“MI:0915”(physical association)	0.850
RNF5	UBE2D3	psi-mi:“MI:0915”(physical association)	0.840
UBE2D3	RNF5	psi-mi:“MI:0915”(physical association)	0.840
UBE2D3	MID1	psi-mi:“MI:0915”(physical association)	0.830
MID1	UBE2D3	psi-mi:“MI:0915”(physical association)	0.830
UBE2D3	TRIM39	psi-mi:“MI:0915”(physical association)	0.800
TRIM39	UBE2D3	psi-mi:“MI:0915”(physical association)	0.800
RNF115	UBE2D3	psi-mi:“MI:0915”(physical association)	0.780
UBE2D3	RNF115	psi-mi:“MI:0915”(physical association)	0.780

BioGRID (958): UBE2D3 (Reconstituted Complex), UBE2D3 (Reconstituted Complex), UBE2D3 (Reconstituted Complex), UBE2D3 (Reconstituted Complex), UBE2D3 (Reconstituted Complex), UBE2D3 (Reconstituted Complex), UBE2D3 (Reconstituted Complex), UBE2D3 (Reconstituted Complex), UBE2D3 (Biochemical Activity), UBE2D3 (Co-crystal Structure), RNF26 (Two-hybrid), UBE2D3 (Reconstituted Complex), UBE2D3 (Reconstituted Complex), UBE2D3 (Reconstituted Complex), UBE2D3 (Reconstituted Complex)

ESM2 similar proteins: A0A1B0GUS4, A5PKP9, D3ZDK2, O13685, O14933, O74196, P15731, P15732, P25867, P35129, P35131, P35132, P35133, P35134, P35135, P43102, P46595, P51668, P52487, P60604, P60605, P61077, P61078, P61079, P61080, P62837, P62838, P62839, P62840, P68037, P70711, Q06AA9, Q17QG5, Q1RMX2, Q2TA10, Q3MHP1, Q3ZCF7, Q4R5N4, Q5R4V7, Q5R5I4

Diamond homologs: A0A1B0GUS4, A5PJC4, A5PKP9, D3ZDK2, O13685, O14933, O74196, O74810, P0C8G3, P0C8G4, P0C8G5, P15731, P15732, P21734, P25867, P25869, P27949, P35128, P35129, P35131, P35132, P35133, P35134, P35135, P43102, P46595, P49427, P51668, P51965, P52482, P52483, P52485, P52487, P52490, P52492, P61077, P61078, P61079, P61080, P61088

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
SNAI2	“down-regulates quantity by repression”	UBE2D3	“transcriptional regulation”
CTBP1	“down-regulates quantity by repression”	UBE2D3	“transcriptional regulation”
HDAC1	“down-regulates quantity by repression”	UBE2D3	“transcriptional regulation”
“Ub:E1 (UBA1 substrate)”	“up-regulates activity”	UBE2D3	ubiquitination
“Ub:E1 (UBA6 substrate)”	“up-regulates activity”	UBE2D3	ubiquitination
UBE2D3	“up-regulates activity”	ZSWIM2	binding
UBE2D3	“up-regulates activity”	MPG	binding
UBE2D3	“up-regulates activity”	UBR5	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 95 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
ER Quality Control Compartment (ERQC)	5	40.0×	1e-05
N-glycan trimming in the ER and Calnexin/Calreticulin cycle	5	31.1×	3e-05
Interferon gamma signaling	11	20.3×	7e-10
Class I MHC mediated antigen processing & presentation	14	14.4×	1e-10
Antigen processing: Ubiquitination & Proteasome degradation	25	13.7×	8e-20
Adaptive Immune System	14	6.1×	5e-06

GO biological processes:

GO term	Partners	Fold	FDR
suppression of viral release by host	7	76.2×	2e-10
negative regulation of viral transcription	5	57.9×	8e-07
host-mediated suppression of symbiont invasion	6	46.3×	1e-07
protein autoubiquitination	16	41.1×	6e-20
protein K63-linked ubiquitination	14	41.1×	2e-17
protein K48-linked ubiquitination	15	27.8×	5e-16
protein polyubiquitination	21	26.6×	3e-22
ubiquitin-dependent protein catabolic process	32	26.1×	1e-34

Disease & clinical

Clinical variants and AI predictions

ClinVar

30 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	1
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1167 predictions. Top by Δscore:

Variant	Effect	Δscore
4:102799401:A:AC	donor_gain	1.0000
4:102799402:C:CC	donor_gain	1.0000
4:102799402:CTTA:C	donor_gain	1.0000
4:102799403:TTA:T	donor_loss	1.0000
4:102799404:TA:T	donor_loss	1.0000
4:102799405:A:AC	donor_gain	1.0000
4:102799406:C:CA	donor_gain	1.0000
4:102799406:CT:C	donor_gain	1.0000
4:102799406:CTT:C	donor_gain	1.0000
4:102799406:CTTA:C	donor_gain	1.0000
4:102799406:CTTAT:C	donor_gain	1.0000
4:102799410:T:C	donor_gain	1.0000
4:102799496:AAGAA:A	acceptor_gain	1.0000
4:102799497:AGAA:A	acceptor_gain	1.0000
4:102799498:GAA:G	acceptor_gain	1.0000
4:102799499:AA:A	acceptor_gain	1.0000
4:102799500:ACTGC:A	acceptor_loss	1.0000
4:102799501:C:CA	acceptor_loss	1.0000
4:102799501:C:CC	acceptor_gain	1.0000
4:102801449:TTTA:T	donor_loss	1.0000
4:102801450:TTA:T	donor_loss	1.0000
4:102801451:TA:T	donor_loss	1.0000
4:102801452:A:T	donor_loss	1.0000
4:102801453:C:G	donor_loss	1.0000
4:102802635:CATT:C	acceptor_gain	1.0000
4:102802636:ATT:A	acceptor_gain	1.0000
4:102802636:ATTC:A	acceptor_loss	1.0000
4:102802637:TT:T	acceptor_gain	1.0000
4:102802637:TTC:T	acceptor_loss	1.0000
4:102802639:C:CA	acceptor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000025929 (4:102829277 C>CTTA), RS1000049983 (4:102851579 G>A,C), RS1000101061 (4:102869232 A>T), RS1000107627 (4:102820225 T>C), RS1000172066 (4:102848550 C>G), RS1000203165 (4:102848301 A>G), RS1000222994 (4:102795381 T>C), RS1000259315 (4:102832703 T>C), RS1000279898 (4:102804449 T>C,G), RS1000281289 (4:102858109 C>A,T), RS1000332924 (4:102822266 T>C), RS1000348281 (4:102822604 T>A), RS1000379354 (4:102820751 A>C), RS1000394996 (4:102804677 GTT>G,GTTT), RS1000435573 (4:102827064 G>A,C,T)

Disease associations

OMIM: gene MIM:602963 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST006630_64	Diastolic blood pressure	4.000000e-21
GCST008919_4	Asthma and attention deficit hyperactivity disorder	3.000000e-08
GCST011377_3	Shoulder impingement or rotator cuff tear	4.000000e-08
GCST90011898_161	Alanine aminotransferase levels	6.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006336	diastolic blood pressure

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105911 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

5 potent at pChembl≥5 of 5 total, top 5 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.55	Kd	283	nM	CHEMBL4080789
6.45	Kd	353	nM	CHEMBL4071335
5.59	Kd	2580	nM	CHEMBL4082171
5.44	Kd	3640	nM	CHEMBL4100955
5.19	Kd	6400	nM	CHEMBL4098033

PubChem BioAssay actives

5 with measured affinity, of 121 total; 5 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(3aS,9bR)-8-[(2-bromophenyl)methoxy]-6,9-dimethyl-3-methylidene-3a,4,5,9b-tetrahydrobenzo[g][1]benzofuran-2-one	1475698: Binding affinity to human recombinant UbcH5c by SPR analysis	kd	0.2830	uM
[(3aS,5aS,8S,9R,9bS)-5a,9-dimethyl-3-methylidene-2-oxo-4,5,6,7,8,9,9a,9b-octahydro-3aH-benzo[g][1]benzofuran-8-yl] 4-iodobenzoate	1475698: Binding affinity to human recombinant UbcH5c by SPR analysis	kd	0.3530	uM
(3aR,5S,8R,8aR,9aR)-8-hydroxy-5,8a-dimethyl-3-methylidene-5,6,7,8,9,9a-hexahydro-3aH-benzo[f][1]benzofuran-2-one	1475698: Binding affinity to human recombinant UbcH5c by SPR analysis	kd	2.5800	uM
[(3aS,6R,8S,9bS)-6-acetyloxy-6,9-dimethyl-3-methylidene-2-oxo-4,5,6a,7,8,9b-hexahydro-3aH-azuleno[4,5-b]furan-8-yl] 4-chlorobenzoate	1475698: Binding affinity to human recombinant UbcH5c by SPR analysis	kd	3.6400	uM
[(3aS,5aS,8S,9R,9bS)-5a,9-dimethyl-3-methylidene-2-oxo-4,5,6,7,8,9,9a,9b-octahydro-3aH-benzo[g][1]benzofuran-8-yl] 3-iodobenzoate	1475698: Binding affinity to human recombinant UbcH5c by SPR analysis	kd	6.4000	uM

CTD chemical–gene interactions

57 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, increases expression	3
Cadmium	increases abundance, increases expression	3
bisphenol A	affects expression, increases expression	2
sodium arsenite	decreases expression, increases expression	2
(+)-JQ1 compound	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	increases expression	2
Valproic Acid	decreases expression	2
Cadmium Chloride	increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
1-hydroxyalantolactone	decreases activity, affects binding	1
bisphenol F	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	decreases expression, increases oxidation, increases abundance, affects cotreatment	1
sodium arsenate	increases expression, increases abundance	1
testosterone undecanoate	decreases expression, affects cotreatment	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
potassium chromate(VI)	decreases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
beta-methylcholine	affects expression	1
dinophysistoxin 1	increases expression	1
di-n-butylphosphoric acid	affects expression	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
candoxin	increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
jinfukang	decreases expression	1

ChEMBL screening assays

18 unique, capped per target: 18 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4030854	Binding	Inhibition of UbcH5c (unknown origin) expressed in human 293T cells assessed as decrease in TNF-alpha-mediated NF-kB activation at 5 uM preincubated for 2 hrs followed by TNF-alpha stimulation for 8 hrs by luciferase reporter gene assay rel	Discovery of Potent Small-Molecule Inhibitors of Ubiquitin-Conjugating Enzyme UbcH5c from α-Santonin Derivatives. — J Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_TV58	HAP1 UBE2D3 (-) 1	Cancer cell line	Male
CVCL_TV59	HAP1 UBE2D3 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.