UBE2L3

Summary

UBE2L3 (ubiquitin conjugating enzyme E2 L3, HGNC:12488) is a protein-coding gene on chromosome 22q11.21, encoding Ubiquitin-conjugating enzyme E2 L3 (P68036). Ubiquitin-conjugating enzyme E2 that specifically acts with HECT-type and RBR family E3 ubiquitin-protein ligases. It is a common-essential gene (DepMap: required in 95.0% of cancer 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 (E1s), ubiquitin-conjugating enzymes (E2s) and ubiquitin-protein ligases (E3s). This gene encodes a member of the E2 ubiquitin-conjugating enzyme family. This enzyme is demonstrated to participate in the ubiquitination of p53, c-Fos, and the NF-kB precursor p105 in vitro. Several alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 7332 — RefSeq curated summary.

At a glance

• Gene–disease (curated): systemic lupus erythematosus (Supportive, GenCC)
• GWAS associations: 91
• Clinical variants (ClinVar): 19 total
• Phenotypes (HPO): 44
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 95.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_003347

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12488
Approved symbol	UBE2L3
Name	ubiquitin conjugating enzyme E2 L3
Location	22q11.21
Locus type	gene with protein product
Status	Approved
Aliases	UBCH7
Ensembl gene	ENSG00000185651
Ensembl biotype	protein_coding
OMIM	603721
Entrez	7332

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 8 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000342192, ENST00000458578, ENST00000496722, ENST00000545681, ENST00000696046, ENST00000877838, ENST00000877839, ENST00000877840, ENST00000920161, ENST00000920162

RefSeq mRNA: 3 — MANE Select: NM_003347 NM_001256355, NM_001256356, NM_003347

CCDS: CCDS13790, CCDS58795, CCDS58796

Canonical transcript exons

ENST00000342192 — 4 exons

Exon	Start	End
ENSE00003575779	21610857	21611043
ENSE00003653912	21592861	21592956
ENSE00003903466	21621515	21624034
ENSE00003965886	21567714	21567771

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 95.73.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.5558 / max 576.1547, expressed in 1810 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
191187	25.5558	1810

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	95.73	gold quality
secondary oocyte	CL:0000655	95.43	gold quality
mucosa of transverse colon	UBERON:0004991	95.23	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.22	gold quality
right frontal lobe	UBERON:0002810	95.14	gold quality
islet of Langerhans	UBERON:0000006	94.87	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.72	gold quality
smooth muscle tissue	UBERON:0001135	94.69	gold quality
cingulate cortex	UBERON:0003027	94.62	gold quality
anterior cingulate cortex	UBERON:0009835	94.56	gold quality
amygdala	UBERON:0001876	94.49	gold quality
spinal cord	UBERON:0002240	94.41	gold quality
lower esophagus	UBERON:0013473	94.37	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.36	gold quality
rectum	UBERON:0001052	94.32	gold quality
leukocyte	CL:0000738	94.31	gold quality
monocyte	CL:0000576	94.30	gold quality
popliteal artery	UBERON:0002250	94.28	gold quality
gastrocnemius	UBERON:0001388	94.27	gold quality
tibial artery	UBERON:0007610	94.27	gold quality
mononuclear cell	CL:0000842	94.22	gold quality
granulocyte	CL:0000094	94.14	gold quality
prefrontal cortex	UBERON:0000451	94.11	gold quality
right adrenal gland	UBERON:0001233	94.11	gold quality
hypothalamus	UBERON:0001898	94.09	gold quality
cortical plate	UBERON:0005343	94.03	gold quality
right adrenal gland cortex	UBERON:0035827	93.97	gold quality
left adrenal gland	UBERON:0001234	93.95	gold quality
muscle of leg	UBERON:0001383	93.95	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.95	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-88	yes	4.02
E-MTAB-8060	no	726.26
E-MTAB-7606	no	465.22
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, CEBPA, TP53

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 95.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 38)

• 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)
• UBE2L3, the c-myc-regulated gene is involved in genotype-C-HBV-related HCC, suggesting that c-myc is related to the hepatocarcinogenic activity of genotype-C HBV. (PMID:16703398)
• identification of the amino acid residues responsible for the HECT-E2 interaction, and for the dynamical properties of the ubiquitin transfer process, may be of relevant interest for pharmacological and therapeutical purposes (PMID:18805400)
• These data suggest a role for UbcH7 targets in the completion of cell cycle S phase and entry into G2. (PMID:18946090)
• The results imply that the interaction specificity between c-Cbl, UbcH7 and UbcH5b is required but not sufficient for transfer of ubiquitin to potential targets. (PMID:18996392)
• UbcH7 charged with ubiquitin has an affinity for E6-associated protein (E6AP) similar to that of uncharged UbcH7. (PMID:20039703)
• Genetic variations of UBE2L3 and BCL3 are potential new risk genes for Crohn’s disease. (PMID:20601676)
• UBCH7 exhibits activity with the RING-in-between-RING (RBR) family of E3s that includes parkin (also known as PARK2) and human homologue of ariadne (HHARI; also known as ARIH1) (PMID:21532592)
• The interaction between UBE2L3 genotype and autoantibodies upon serum IFN-alpha suggests a biological role for this locus in patients with systemic lupus erythematosus. (PMID:22045845)
• UBE2L3 was found to be a shared susceptibility gene for siffuse cutaneous systemic sclerosis in a Japanese population. (PMID:22294623)
• Crystal structures of two bacterial E3s, Salmonella SopA and Escherichia coli NleL, both in complex with human E2 UbcH7, are reported. (PMID:22308380)
• The results suggest that variants carried on the SLE-associated UBE2L3 risk haplotype influence autoimmunity by modulating UBCH7 expression. (PMID:22476155)
• Report role of UBE2L3 genetic variants in confering risk of systemic lupus erythematosus in Chinese population. (PMID:24091983)
• Importance of HLA-C and UBE2L3 in the clearance of HBV infection in addition to HLA-DP and HLA-DQ. (PMID:24162738)
• An interaction between LC1 and the ubiquitin-conjugating enzyme UBE2L3. (PMID:24566975)
• together with UBE2N and UBE2D2, synergistically contribute to Parkin-mediated mitophagy (PMID:24906799)
• UbcH7 has a role in regulating 53BP1 stability and DSB repair (PMID:25422456)
• The MAP1B-LC1 could interact with the ubiquitin-conjugating E2 enzyme UBE2L3 and that the ubiquitination/degradation mechanism triggered by MAP1B-LC1 could be prevented by inhibiting the ubiquitin-proteasome proteolytic pathway. (PMID:25483588)
• UBE2L3 polymorphism amplifies NF-kappaB activation and promotes plasma cell development, linking linear ubiquitination to multiple autoimmune diseases. (PMID:25640675)
• The TCGGC haplotype is associated with an increased risk of Hashimoto Thyroiditis(HT) and UBE2L3 gene is likely to be a susceptibility factor to HT in a Chinese Han population. (PMID:27094594)
• Crystal structure of HHARI and UbcH7 reveals UbcH7 approximately Ub binding RING1 domain of auto-inhibited HHARI. (PMID:28552575)
• Data suggest ordered binding of UBCH7-ubiquitin to E6AP Site 1 (for E6AP-Cys820/ubiquitin thioester formation) and E6AP Site 2 (for subsequent chain elongation); proximal indexation accounts for radially symmetric structure of E6AP, requirement for oligomerization in polyubiquitin chain formation, and mechanistic rationale for Cys820-ubiquitin thioester as platform in chain assembly. (E6AP = ubiquitin-protein ligase E6AP) (PMID:28924046)
• Low UBE2L3 expression is associated with chikungunya fever. (PMID:28975709)
• The association between the genotype of rs4821116 in the UBE2L3 gene and the reduction in viral load in pregnant women needed to be confirmed by studies with a larger sample size. (PMID:29056010)
• The variant genotypes of rs4821116 in ubiquitin conjugating enzyme E2 L3 (UBE2L3) are associated with decreased risk for HBV-related hepatocellular carcinoma (HCC) and chronic hepatitis B virus (HBV) infection. Higher levels of UBE2L3 expression are correlated with higher tumor grade, advanced tumor stage and poor survival. In vitro analysis revealed that UBE2L3 may promote hepatocyte proliferation and migration. (PMID:29969176)
• UBCH7/UBE2L3 catalyzes the conjugation of heterotypic ubiquitin chains on p27(Kip1) that are proteolytically incompetent (PMID:30113882)
• Synergistic recruitment of UbcH7~Ub and phosphorylated Ubl domain triggers parkin activation. (PMID:30446597)
• The rs59391722 allele in the promoter of the UBE2L3 gene was significantly associated with hepatitis B in both adults and children, and it increased the promoter activity of UBE2L3. Serum UBE2L3 protein levels were positively correlated with HBV viral load and hepatitis B e antigen levels in children with chronic hepatitis B. (PMID:30614547)
• Overexpression of ubiquitin-conjugating enzyme E2 L3 in hepatocellular carcinoma potentiates apoptosis evasion by inhibiting the GSK3beta/p65 pathway. (PMID:32268166)
• Synergistic activation of NF-kappaB by TNFAIP3 (A20) reduction and UBE2L3 (UBCH7) augment that synergistically elevate lupus risk. (PMID:32334614)
• Variants on the UBE2L3/YDJC Autoimmune Disease Risk Haplotype Increase UBE2L3 Expression by Modulating CCCTC-Binding Factor and YY1 Binding. (PMID:34279042)
• UBE2L3 promotes squamous cell carcinoma progression in the oral cavity and hypopharynx via activating the NF-kappaB signaling by increasing IkappaBalpha degradation. (PMID:35128752)
• UBE2L3 Reduces TRIM21 Expression and IL-1beta Secretion in Epidermal Keratinocytes and Improves Psoriasis-Like Skin. (PMID:36502938)
• UBE2L3 regulates TLR7-induced B cell autoreactivity in Systemic Lupus Erythematosus. (PMID:37001433)
• The membrane-associated ubiquitin ligase MARCHF8 stabilizes the human papillomavirus oncoprotein E7 by degrading CUL1 and UBE2L3 in head and neck cancer. (PMID:38226814)
• The E3 ligase SMURF1 stabilizes p27 via UbcH7 catalyzed K29-linked ubiquitin chains to promote cell migration SMURF1-UbcH7 K29 ubiquitination of p27 and cell migration. (PMID:38301893)
• UBE2L3 expression in human gastric cancer and its clinical significance. (PMID:38656363)
• Role of Ubiquitin-conjugating enzyme E2 (UBE2) in two immune-mediated inflammatory skin diseases: a mendelian randomization analysis. (PMID:38795139)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ube2l3b	ENSDARG00000027141
danio_rerio	ube2l3a	ENSDARG00000112087
mus_musculus	Ube2l3	ENSMUSG00000038965
rattus_norvegicus	Ube2l3	ENSRNOG00000001862

Paralogs (12): UBE2D1 (ENSG00000072401), UBE2D4 (ENSG00000078967), UBE2D3 (ENSG00000109332), UBE2D2 (ENSG00000131508), UBE2Q2 (ENSG00000140367), UBE2L6 (ENSG00000156587), UBE2Q1 (ENSG00000160714), UBE2E3 (ENSG00000170035), UBE2E1 (ENSG00000170142), UBE2E2 (ENSG00000182247), UBE2QL1 (ENSG00000215218), UBE2L5 (ENSG00000236444)

Protein

Protein identifiers

Ubiquitin-conjugating enzyme E2 L3 — P68036 (reviewed: P68036)

Alternative names: E2 ubiquitin-conjugating enzyme L3, L-UBC, UbcH7, Ubiquitin carrier protein L3, Ubiquitin-conjugating enzyme E2-F1, Ubiquitin-protein ligase L3

All UniProt accessions (2): A0A8Q3WL22, P68036

UniProt curated annotations — full annotation on UniProt →

Function. Ubiquitin-conjugating enzyme E2 that specifically acts with HECT-type and RBR family E3 ubiquitin-protein ligases. Does not function with most RING-containing E3 ubiquitin-protein ligases because it lacks intrinsic E3-independent reactivity with lysine; in contrast, it has activity with the RBR family E3 enzymes, such as PRKN, RNF31 and ARIH1, that function like RING-HECT hybrids. Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. Mediates ubiquitination by the CUL9-RBX1 complex. In vitro catalyzes ‘Lys-11’-linked polyubiquitination. Involved in the selective degradation of short-lived and abnormal proteins. Down-regulated during the S-phase it is involved in progression through the cell cycle. Regulates nuclear hormone receptors transcriptional activity. May play a role in myelopoiesis.

Subunit / interactions. Interacts with PRKN; involved in ubiquitination and degradation of misfolded proteins. Interacts with UBE3A; used by the papilloma virus HPV-16 E6 protein to ubiquitinate p53/TP53. Interacts with CCNB1IP1, CBL, ZAP70, RNF19A, RNF19B and RNF144B. Interacts with ARIH1. Interacts with ARIH2 (via RING-type 1). Interacts with NCOA1; they functionally interact to regulate progesterone receptor transcriptional activity. May interact with NR3C1. Interacts with NDFIP1 (via N-terminus); the interaction mediates recruitment of UBE2L3 to ITCH and causes MAP3K7 ubiquitination.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Ubiquitous, with highest expression in testis.

Post-translational modifications. Ubiquitinated. The alteration of UBE2L3 protein levels during the S-phase of the cell cycle is due to ubiquitin-dependent proteasomal degradation. Autoubiquitinated in vitro.

Domain organisation. In contrast to other ubiquitin-conjugating enzymes E2, residues essential for lysine reactivity are absent: Pro and a His residues are present instead of an Asp and an Asp residues in positions 88 and 119, respectively.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the ubiquitin-conjugating enzyme family.

Isoforms (3)

UniProt ID	Names	Canonical?
P68036-1	1	yes
P68036-2	2
P68036-3	3

RefSeq proteins (3): NP_001243284, NP_001243285, NP_003338* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000608	UBC	Domain
IPR016135	UBQ-conjugating_enzyme/RWD	Homologous_superfamily
IPR023313	UBQ-conjugating_AS	Active_site
IPR050113	Ub_conjugating_enzyme-E2-like	Family

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): mutagenesis site 8, strand 7, helix 5, turn 4, sequence conflict 3, splice variant 2, chain 1, domain 1, active site 1, modified residue 1

Structure

Experimental structures (PDB)

21 structures.

PDB	Method	Resolution (Å)
7V8F	X-RAY DIFFRACTION	1.66
4Q5E	X-RAY DIFFRACTION	1.87
4Q5H	X-RAY DIFFRACTION	2
1C4Z	X-RAY DIFFRACTION	2.6
5HPT	X-RAY DIFFRACTION	2.84
1FBV	X-RAY DIFFRACTION	2.9
6CP2	X-RAY DIFFRACTION	2.9
8EB0	X-RAY DIFFRACTION	3.03
8EAZ	X-RAY DIFFRACTION	3.08
5UDH	X-RAY DIFFRACTION	3.24
3SY2	X-RAY DIFFRACTION	3.27
3SQV	X-RAY DIFFRACTION	3.3
7OIK	ELECTRON MICROSCOPY	3.5
5TTE	X-RAY DIFFRACTION	3.5
7B5N	ELECTRON MICROSCOPY	3.6
7B5L	ELECTRON MICROSCOPY	3.8
9I1J	ELECTRON MICROSCOPY	3.8
6DJW	X-RAY DIFFRACTION	3.8
6DJX	X-RAY DIFFRACTION	4.8
6N13	SOLUTION NMR
6XXU	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P68036-F1	95.70	0.94

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): 86 (glycyl thioester intermediate)

Post-translational modifications (1): 131

Mutagenesis-validated functional residues (8):

Position	Phenotype
93	decrease in autoubiquitination.
96	decrease in autoubiquitination.
100	decrease in autoubiquitination.
119	does not convert into a lysine reactive e2; when associated with d-88.
9	marked decrease in autoubiquitination.
63	decrease in autoubiquitination. abolishes ubiquitination of tp53 by the cul9-rbx1 complex.
86	loss of catalytic activity. prevents ubiquitin-dependent proteasomal degradation of ube2l3.
88	does not convert into a lysine reactive e2; when associated with d-119.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-5205685	PINK1-PRKN Mediated Mitophagy
R-HSA-5357905	Regulation of TNFR1 signaling
R-HSA-5675482	Regulation of necroptotic cell death
R-HSA-8866652	Synthesis of active ubiquitin: roles of E1 and E2 enzymes
R-HSA-8866654	E3 ubiquitin ligases ubiquitinate target proteins
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 374 (showing top): AGGAAGC_MIR5163P, MORF_SMC1L1, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_CELLULAR_RESPONSE_TO_LIPID, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_RESPONSE_TO_CORTICOSTEROID, TTTGTAG_MIR520D, GCM_NPM1, MORF_UBE2I, GOBP_CELL_CYCLE_PHASE_TRANSITION, MORF_HDAC1, MORF_UBE2N, GOBP_PROTEIN_TARGETING, GOBP_MACROMOLECULE_CATABOLIC_PROCESS

GO Biological Process (14): protein polyubiquitination (GO:0000209), regulation of DNA-templated transcription (GO:0006355), ubiquitin-dependent protein catabolic process (GO:0006511), cell population proliferation (GO:0008283), protein ubiquitination (GO:0016567), positive regulation of protein ubiquitination (GO:0031398), protein modification process (GO:0036211), cell cycle phase transition (GO:0044770), protein K11-linked ubiquitination (GO:0070979), cellular response to steroid hormone stimulus (GO:0071383), cellular response to glucocorticoid stimulus (GO:0071385), obsolete positive regulation of protein targeting to mitochondrion (GO:1903955), protein modification by small protein conjugation (GO:0032446), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (12): transcription coactivator activity (GO:0003713), RNA binding (GO:0003723), ubiquitin-protein transferase activity (GO:0004842), ATP binding (GO:0005524), enzyme binding (GO:0019899), ubiquitin protein ligase binding (GO:0031625), ubiquitin conjugating enzyme activity (GO:0061631), ubiquitin-protein transferase activator activity (GO:0097027), nucleotide binding (GO:0000166), protein binding (GO:0005515), transferase activity (GO:0016740), ubiquitin-like protein transferase activity (GO:0019787)

GO Cellular Component (5): ubiquitin ligase complex (GO:0000151), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Protein ubiquitination	2
Mitophagy	1
TNF signaling	1
RIPK1-mediated regulated necrosis	1
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein ubiquitination	3
cellular anatomical structure	3
DNA-templated transcription	2
ubiquitin-protein transferase activity	2
regulation of gene expression	1
regulation of RNA biosynthetic process	1
modification-dependent protein catabolic process	1
cellular process	1
protein modification by small protein conjugation	1
regulation of protein ubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
protein metabolic process	1
macromolecule modification	1
cell cycle process	1
protein polyubiquitination	1
cellular response to hormone stimulus	1
response to steroid hormone	1
cellular response to lipid	1
response to glucocorticoid	1
cellular response to corticosteroid stimulus	1
protein modification by small protein conjugation or removal	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
transcription coregulator activity	1
positive regulation of DNA-templated transcription	1
nucleic acid binding	1
ubiquitin-like protein transferase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
protein binding	1
ubiquitin-like protein ligase binding	1
ubiquitin-like protein conjugating enzyme activity	1
enzyme activator activity	1
ubiquitin-protein transferase regulator activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
aminoacyltransferase activity	1
catalytic activity, acting on a protein	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

114 interactions, top by confidence:

A	B	Type	Score
ARIH2	UBE2L3	psi-mi:“MI:0915”(physical association)	0.880
UBE2L3	ARIH2	psi-mi:“MI:0915”(physical association)	0.880
ARIH2	UBE2L3	psi-mi:“MI:0914”(association)	0.880
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
RNF144A	UBE2L3	psi-mi:“MI:0915”(physical association)	0.670
UBE2L3	RBCK1	psi-mi:“MI:0915”(physical association)	0.670
MID1	UBE2L3	psi-mi:“MI:0915”(physical association)	0.670
ARIH1	UBE2L3	psi-mi:“MI:0914”(association)	0.640
UBE2L3		psi-mi:“MI:0915”(physical association)	0.560
UBE2L3	RNF216	psi-mi:“MI:0915”(physical association)	0.560
	UBE2L3	psi-mi:“MI:0915”(physical association)	0.560
UBE2L3	RNF182	psi-mi:“MI:0915”(physical association)	0.560
PRKN	UBE2L3	psi-mi:“MI:0915”(physical association)	0.560
STUB1	UBE2L3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (701): ARIH1 (Reconstituted Complex), UBE2L3 (Two-hybrid), ARIH2 (Two-hybrid), UBE2L3 (Reconstituted Complex), ARIH2 (Two-hybrid), UBE2L3 (Reconstituted Complex), UBE2L3 (Reconstituted Complex), UBE2L3 (Reconstituted Complex), UBE2L3 (Reconstituted Complex), UBE2L3 (Reconstituted Complex), UBE2L3 (Reconstituted Complex), UBE2L3 (Reconstituted Complex), UBE2L3 (Reconstituted Complex), UBE2L3 (Affinity Capture-Western), UBE2L3 (Biochemical Activity)

ESM2 similar proteins: A0A1B0GUS4, A5PJC4, A5PKP9, D3ZDK2, O13685, O14933, O74196, O74549, P15731, P15732, P25867, P35129, P35131, P35132, P35133, P35134, P35135, P43102, P51668, P52487, P60604, P60605, P61080, P62837, P62838, P62839, P62840, P68036, P68037, P70711, Q17QG5, Q1RMX2, Q21633, Q2TA10, Q3MHP1, Q3ZCF7, Q4V8J2, Q5R5I4, Q5RF84, Q6C9W0

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

5 interactions.

A	Effect	B	Mechanism
“Ub:E1 (UBA1 substrate)”	“up-regulates activity”	UBE2L3	ubiquitination
“Ub:E1 (UBA6 substrate)”	“up-regulates activity”	UBE2L3	ubiquitination
UBE2L3	“up-regulates activity”	RNF19B	binding
UBE2L3	“up-regulates activity”	PRKN	ubiquitination
UBE2L3	“up-regulates activity”	NEDD4	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 78 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
DDX58/IFIH1-mediated induction of interferon-alpha/beta	5	20.5×	1e-03
Activation of STAT3 by cadherin engagement	5	13.2×	3e-03
Antigen processing: Ubiquitination & Proteasome degradation	18	10.8×	1e-11

GO biological processes:

GO term	Partners	Fold	FDR
protein autoubiquitination	6	18.7×	1e-04
protein polyubiquitination	12	18.5×	4e-10
protein K63-linked ubiquitination	5	17.8×	8e-04
ubiquitin-dependent protein catabolic process	16	15.8×	1e-12
positive regulation of protein ubiquitination	5	14.2×	2e-03
protein K48-linked ubiquitination	6	13.5×	6e-04
protein ubiquitination	20	11.0×	5e-13
proteasome-mediated ubiquitin-dependent protein catabolic process	10	7.0×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	4
Likely benign	0
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1246 predictions. Top by Δscore:

Variant	Effect	Δscore
22:21592957:G:GG	donor_gain	1.0000
22:21610855:A:AG	acceptor_gain	1.0000
22:21610855:AG:A	acceptor_gain	1.0000
22:21610856:G:GC	acceptor_gain	1.0000
22:21610856:GG:G	acceptor_gain	1.0000
22:21610856:GGA:G	acceptor_gain	1.0000
22:21610856:GGAC:G	acceptor_gain	1.0000
22:21610856:GGACA:G	acceptor_gain	1.0000
22:21611041:AAG:A	donor_gain	1.0000
22:21611041:AAGG:A	donor_loss	1.0000
22:21611042:AG:A	donor_gain	1.0000
22:21611042:AGGT:A	donor_loss	1.0000
22:21611043:GG:G	donor_gain	1.0000
22:21611043:GGT:G	donor_loss	1.0000
22:21611044:G:GA	donor_loss	1.0000
22:21611044:G:GG	donor_gain	1.0000
22:21611045:T:G	donor_loss	1.0000
22:21621513:A:AG	acceptor_gain	1.0000
22:21621514:G:GA	acceptor_gain	1.0000
22:21621514:GTA:G	acceptor_gain	1.0000
22:21567759:G:GT	donor_gain	0.9900
22:21567767:TGAAG:T	donor_loss	0.9900
22:21567769:AAGGT:A	donor_loss	0.9900
22:21567770:AGG:A	donor_loss	0.9900
22:21567771:GGTAA:G	donor_loss	0.9900
22:21567772:GT:G	donor_loss	0.9900
22:21567773:T:A	donor_loss	0.9900
22:21592852:A:AG	acceptor_gain	0.9900
22:21592855:CAACA:C	acceptor_loss	0.9900
22:21592858:CA:C	acceptor_loss	0.9900

AlphaMissense

1029 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:21567761:G:T	R6M	1.000
22:21611016:T:A	W95R	1.000
22:21611016:T:C	W95R	1.000
22:21611018:G:C	W95C	1.000
22:21611018:G:T	W95C	1.000
22:21567762:G:C	R6S	0.999
22:21567762:G:T	R6S	0.999
22:21592936:T:A	W35R	0.999
22:21592936:T:C	W35R	0.999
22:21610884:T:C	F51L	0.999
22:21610885:T:C	F51S	0.999
22:21610886:C:A	F51L	0.999
22:21610886:C:G	F51L	0.999
22:21610920:T:C	F63L	0.999
22:21610922:C:A	F63L	0.999
22:21610922:C:G	F63L	0.999
22:21610967:C:A	N78K	0.999
22:21610967:C:G	N78K	0.999
22:21610980:G:A	G83R	0.999
22:21610980:G:C	G83R	0.999
22:21611017:G:C	W95S	0.999
22:21621527:T:C	L108P	0.999
22:21621536:T:C	L111P	0.999
22:21621610:T:C	F136L	0.999
22:21621612:C:A	F136L	0.999
22:21621612:C:G	F136L	0.999
22:21621623:C:A	A140D	0.999
22:21567760:A:T	R6W	0.998
22:21567761:G:C	R6T	0.998
22:21592861:G:A	E10K	0.998

dbSNP variants (sampled 300 via entrez): RS1000003565 (22:21558934 T>C), RS1000026276 (22:21604557 G>C), RS1000070009 (22:21556459 T>G), RS1000085025 (22:21598284 C>T), RS1000091452 (22:21605979 C>G), RS1000152353 (22:21622405 G>C), RS1000226425 (22:21622650 C>T), RS1000283989 (22:21581282 C>T), RS1000296519 (22:21574862 G>C), RS1000326501 (22:21593158 C>T), RS1000338758 (22:21586614 C>T), RS1000356203 (22:21604314 C>T), RS1000371019 (22:21604908 C>G), RS1000421262 (22:21616778 G>A), RS1000448848 (22:21619477 T>C)

Disease associations

OMIM: gene MIM:603721 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
systemic lupus erythematosus	Supportive	Unknown

Mondo (1): systemic lupus erythematosus (MONDO:0007915)

Orphanet (0):

HPO phenotypes

44 total (30 of 44 shown, HPO-id order):

HPO	Term
HP:0000093	Proteinuria
HP:0000155	Oral ulcer
HP:0000488	Retinopathy
HP:0000716	Depression
HP:0000790	Hematuria
HP:0000822	Hypertension
HP:0000992	Cutaneous photosensitivity
HP:0001250	Seizure
HP:0001369	Arthritis
HP:0001596	Alopecia
HP:0001824	Weight loss
HP:0001873	Thrombocytopenia
HP:0001878	Hemolytic anemia
HP:0001882	Decreased total leukocyte count
HP:0001945	Fever
HP:0002039	Anorexia
HP:0002072	Chorea
HP:0002716	Lymphadenopathy
HP:0003453	Antineutrophil antibody positivity
HP:0003493	Antinuclear antibody positivity
HP:0005421	Decreased circulating complement C3 concentration
HP:0005764	Polyarticular arthritis
HP:0007417	Discoid lupus rash
HP:0012085	Pyuria
HP:0012378	Fatigue
HP:0020151	Anti-dsDNA antibody positivity
HP:0025300	Malar rash
HP:0030880	Raynaud phenomenon
HP:0032235	Anti-La/SS-B antibody positivity
HP:0033028	Anti-U1 ribonucleoprotein antibody positivity

GWAS associations

91 associations (top):

Study	Trait	p-value
GCST000507_6	Systemic lupus erythematosus	1.000000e-16
GCST000585_2	Mean corpuscular volume	1.000000e-08
GCST000612_29	Celiac disease	2.000000e-07
GCST000755_14	HDL cholesterol	1.000000e-08
GCST000987_7	Celiac disease or Rheumatoid arthritis	3.000000e-10
GCST000996_10	Systemic lupus erythematosus	2.000000e-06
GCST001725_108	Inflammatory bowel disease	1.000000e-16
GCST001765_28	Red blood cell traits	9.000000e-10
GCST001795_31	Systemic lupus erythematosus	5.000000e-06
GCST002223_62	HDL cholesterol	4.000000e-18
GCST002246_3	Hepatitis B	2.000000e-12
GCST002318_165	Rheumatoid arthritis	2.000000e-07
GCST002318_36	Rheumatoid arthritis	2.000000e-09
GCST002899_29	HDL cholesterol	2.000000e-10
GCST003155_25	Systemic lupus erythematosus	2.000000e-22
GCST003156_5	Systemic lupus erythematosus	3.000000e-13
GCST003620_9	Systemic lupus erythematosus or rheumatoid arthritis	2.000000e-11
GCST003622_43	Systemic lupus erythematosus	1.000000e-13
GCST003622_66	Systemic lupus erythematosus	2.000000e-06
GCST004004_24	Mean corpuscular volume	2.000000e-07
GCST004131_48	Inflammatory bowel disease	4.000000e-15
GCST004132_118	Crohn’s disease	1.000000e-15
GCST004133_48	Ulcerative colitis	9.000000e-06
GCST004232_16	HDL cholesterol levels	1.000000e-22
GCST004232_38	HDL cholesterol levels	4.000000e-08
GCST004234_17	HDL cholesterol levels	3.000000e-06
GCST004602_242	Mean corpuscular volume	1.000000e-37
GCST004605_82	Mean corpuscular hemoglobin concentration	2.000000e-11
GCST004611_167	High light scatter reticulocyte count	2.000000e-14
GCST004612_188	High light scatter reticulocyte percentage of red cells	6.000000e-16

EFO canonical traits (17, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0007986	reticulocyte count
EFO:0009188	Red cell distribution width
EFO:0004587	lymphocyte count
EFO:0004527	mean corpuscular hemoglobin
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes
EFO:0004695	intraocular pressure measurement
EFO:0004574	total cholesterol measurement
EFO:0009270	heel bone mineral density
EFO:0004329	alcohol drinking
EFO:0004614	apolipoprotein A 1 measurement
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0005091	monocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008180	Lupus Erythematosus, Systemic	C17.300.480; C20.111.590

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105871 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.50	Kd	320.2	nM	CHEMBL5653589
6.50	ED50	320.2	nM	CHEMBL5653589
5.24	Kd	5786	nM	CHEMBL3752910
5.24	ED50	5786	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 5 total; 2 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149709: Binding affinity to human UBE2L3 incubated for 45 mins by Kinobead based pull down assay	kd	0.3202	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149709: Binding affinity to human UBE2L3 incubated for 45 mins by Kinobead based pull down assay	kd	5.7859	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects cotreatment	3
sodium arsenite	decreases expression, increases expression	2
Particulate Matter	affects expression, increases reaction, decreases expression	2
methylmercuric chloride	decreases expression	1
bisphenol A	decreases methylation	1
pyrogallol 1,3-dimethyl ether	decreases expression, affects cotreatment, affects localization	1
2-bromopalmitate	increases palmitoylation, decreases reaction, increases abundance	1
benzo(e)pyrene	decreases methylation	1
cupric oxide	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine	increases reaction, affects expression	1
nutlin 3	affects cotreatment, increases secretion	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	increases expression	1
Temozolomide	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Vehicle Emissions	affects expression, increases reaction	1
Benzo(a)pyrene	decreases expression	1
Cadmium	decreases reaction, increases abundance, increases palmitoylation	1
Carcinogens	decreases expression	1
Dactinomycin	affects cotreatment, increases secretion	1
Diacetyl	increases expression	1
Diazinon	decreases methylation	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Formaldehyde	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4030866	Binding	Inhibition of UbcH7 (unknown origin) at 2.5 to 10 uM preincubated for 15 mins followed by E1, Ub and ATP addition measured after 40 mins by Western blot analysis	Discovery of Potent Small-Molecule Inhibitors of Ubiquitin-Conjugating Enzyme UbcH5c from α-Santonin Derivatives. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00120887	PHASE4	COMPLETED	Lupus Atherosclerosis Prevention Study
NCT00125307	PHASE4	COMPLETED	Tacrolimus for the Treatment of Systemic Lupus Erythematosus With Membranous Nephritis
NCT00188188	PHASE4	UNKNOWN	Study of Endothelial Dysfunction in Systemic Lupus and Its Role in Heart Disease
NCT00371501	PHASE4	COMPLETED	Aspirin and Statins for Prevention of Atherosclerosis and Arterial Thromboembolism in Systemic Lupus Erythematosus
NCT00392093	PHASE4	COMPLETED	Effect of Hormone Replacement Therapy on Lupus Activity
NCT00413361	PHASE4	COMPLETED	The Reduction of Systemic Lupus Erythematosus Flares :Study PLUS
NCT00508898	PHASE4	WITHDRAWN	The Efficacy and Safety of Calcitriol for the Treatment of Lupus Nephritis and Persistent Proteinuria
NCT00668330	PHASE4	COMPLETED	Steroid Induced Osteoporosis in Patients With Systemic Lupus Erythematosus
NCT00739050	PHASE4	TERMINATED	Effect of Simvastatin on Endothelial Function in Premenopausal Women With Systemic Lupus Erythematosus (0733-271)(TERMINATED)
NCT00815282	PHASE4	COMPLETED	Immune Response After Human Papillomavirus Vaccination in Patients With Autoimmune Disease
NCT00828178	PHASE4	COMPLETED	Efficacy of Fish Oil in Lupus Patients
NCT00866229	PHASE4	UNKNOWN	Efficacy and Adverse Effect of Simvastatin Compare to Rosuvastatin in Systemic Lupus Erythematosus (SLE) Patients With Corticosteroid Therapy and High Low-Density Lipoprotein (LDL) Cholesterol Level
NCT00911521	PHASE4	COMPLETED	Immunogenicity and Safety of a Quadrivalent Human Papillomavirus (HPV) Vaccine in Patients With SLE: a Controlled Study
NCT01101802	PHASE4	COMPLETED	Mycophenolate Mofetil in Systemic Lupus Erythematosus (MISSILE)
NCT01112215	PHASE4	COMPLETED	Enteric-coated Mycophenolate Sodium Versus Azathioprine for the Extra-renal Lupus Manifestations
NCT01151644	PHASE4	UNKNOWN	Safety and Efficacy of Anti-Pandemic H1N1 Vaccination in Rheumatic Diseases
NCT01276782	PHASE4	WITHDRAWN	Levothyroxine in Pregnant SLE Patients
NCT01322308	PHASE4	COMPLETED	Effect of Pioglitazone on Endothelial Function in Premenopausal Women With Uncomplicated Systemic Lupus Erythematosus
NCT01359826	PHASE4	WITHDRAWN	The Effect of Milnacipran on Fatigue and Quality of Life in Lupus Patients
NCT01597492	PHASE4	COMPLETED	A Study to Evaluate the Effect of Belimumab on Vaccine Responses in Subjects With Systemic Lupus Erythematosus (SLE)
NCT01632241	PHASE4	COMPLETED	Efficacy and Safety of Belimumab in Black Race Patients With Systemic Lupus Erythematosus (SLE)
NCT01705977	PHASE4	COMPLETED	Belimumab Assessment of Safety in SLE
NCT01753401	PHASE4	COMPLETED	Acthar for the Treatment of Systemic Lupus Erythematosus (SLE) in Patients With a History of Persistently Active Disease
NCT02270970	PHASE4	UNKNOWN	Evaluation of Belimumab Impact on a BLyS Activity Signature Test in the Absence of Confounding Polypharmacy
NCT02477150	PHASE4	COMPLETED	Safety and Immunogenicity of a Zoster Vaccine in SLE
NCT02741960	PHASE4	COMPLETED	The Effect of Metformin on Reducing Lupus Flares
NCT02779153	PHASE4	WITHDRAWN	Acthar SLE (Systemic Lupus Erythematosus)
NCT02953821	PHASE4	COMPLETED	Acthar Gel for Active Systemic Lupus Erythematosus (SLE)
NCT03042260	PHASE4	UNKNOWN	Prophylactic Trimethoprim/Sulfamethoxazole to Prevent Severe Infections in Patients With Lupus Erythematous
NCT03098823	PHASE4	COMPLETED	A Crossover Study to Compare RAYOS to IR Prednisone to Improve Fatigue and Morning Symptoms for SLE
NCT03122431	PHASE4	COMPLETED	Relevance of Monitoring Blood and Salivar Levels of Drugs Used in Rheumatic Autoimmune Diseases
NCT03543839	PHASE4	RECRUITING	Trial of Belimumab in Early Lupus
NCT04447053	PHASE4	UNKNOWN	Sequential Belimumab and T-cell Based Therapy in SLE
NCT04515719	PHASE4	COMPLETED	Efficacy and Safety of Belimumab in SLE Patients
NCT04893161	PHASE4	UNKNOWN	A Model About the Response of Belimumab in SLE
NCT04908865	PHASE4	COMPLETED	Open-label Study of Belimumab Plus Standard Therapy in Chinese Pediatric Participants With Active Systemic Lupus Erythematosus (SLE)
NCT04956484	PHASE4	COMPLETED	Belimumab In Early Systemic Lupus Erythematosus
NCT05559671	PHASE4	RECRUITING	Safety of the Herpes Zoster Subunit Vaccine in Lupus
NCT05666336	PHASE4	UNKNOWN	Multi-omics Studies on the Efficacy of Telitacicept in Chinese SLE Patients
NCT05748925	PHASE4	COMPLETED	Cardio Renal Effects of SGLT2 Inhibitors Among Lupus Nephritis Patients