UBC

Summary

UBC (ubiquitin C, HGNC:12468) is a protein-coding gene on chromosome 12q24.3, encoding Polyubiquitin-C (P0CG48). Exists either covalently attached to another protein, or free (unanchored). It is a selective cancer dependency (DepMap: 30.1% of cell lines).

This gene represents a ubiquitin gene, ubiquitin C. The encoded protein is a polyubiquitin precursor. Conjugation of ubiquitin monomers or polymers can lead to various effects within a cell, depending on the residues to which ubiquitin is conjugated. Ubiquitination has been associated with protein degradation, DNA repair, cell cycle regulation, kinase modification, endocytosis, and regulation of other cell signaling pathways.

Source: NCBI Gene 7316 — RefSeq curated summary.

At a glance

• GWAS associations: 14
• Clinical variants (ClinVar): 69 total — 1 likely-pathogenic
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 30.1% of screened cell lines
• MANE Select transcript: NM_021009

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12468
Approved symbol	UBC
Name	ubiquitin C
Location	12q24.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000150991
Ensembl biotype	protein_coding
OMIM	191340
Entrez	7316

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 17 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000339647, ENST00000535131, ENST00000535859, ENST00000536661, ENST00000536769, ENST00000538617, ENST00000540351, ENST00000540700, ENST00000541272, ENST00000541645, ENST00000542416, ENST00000544481, ENST00000546271, ENST00000874892, ENST00000874893, ENST00000964560, ENST00000964561, ENST00000964562, ENST00000964563

RefSeq mRNA: 1 — MANE Select: NM_021009 NM_021009

CCDS: CCDS9260

Canonical transcript exons

ENST00000339647 — 2 exons

Exon	Start	End
ENSE00001406973	124911646	124913774
ENSE00002310511	124914587	124914650

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 866.6041 / max 7320.4345, expressed in 1828 samples.

FANTOM5 promoters (17 alternative TSS)

Promoter ID	TPM avg	Samples expressed
134048	857.9764	1828
134050	3.7608	1550
134049	1.6280	866
134046	1.2801	479
134059	0.4850	220
134051	0.3601	139
134045	0.3027	76
134058	0.1619	68
134043	0.1410	43
134044	0.1370	41

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
olfactory bulb	UBERON:0002264	99.99	gold quality
pericardium	UBERON:0002407	99.98	gold quality
vena cava	UBERON:0004087	99.98	gold quality
cerebellar vermis	UBERON:0004720	99.98	gold quality
Brodmann (1909) area 46	UBERON:0006483	99.98	gold quality
dorsal root ganglion	UBERON:0000044	99.97	gold quality
trigeminal ganglion	UBERON:0001675	99.97	gold quality
parietal lobe	UBERON:0001872	99.97	gold quality
postcentral gyrus	UBERON:0002581	99.97	gold quality
adult organism	UBERON:0007023	99.97	gold quality
pons	UBERON:0000988	99.96	gold quality
substantia nigra pars compacta	UBERON:0001965	99.96	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.96	gold quality
decidua	UBERON:0002450	99.96	gold quality
lateral globus pallidus	UBERON:0002476	99.96	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.96	gold quality
frontal pole	UBERON:0002795	99.96	gold quality
trachea	UBERON:0003126	99.96	gold quality
paraflocculus	UBERON:0005351	99.96	gold quality
saphenous vein	UBERON:0007318	99.96	gold quality
cardia of stomach	UBERON:0001162	99.95	gold quality
mucosa of urinary bladder	UBERON:0001259	99.95	gold quality
dorsal plus ventral thalamus	UBERON:0001897	99.95	gold quality
subthalamic nucleus	UBERON:0001906	99.95	gold quality
gluteal muscle	UBERON:0002000	99.95	gold quality
cartilage tissue	UBERON:0002418	99.95	gold quality
ventral tegmental area	UBERON:0002691	99.95	gold quality
entorhinal cortex	UBERON:0002728	99.95	gold quality
middle temporal gyrus	UBERON:0002771	99.95	gold quality
orbitofrontal cortex	UBERON:0004167	99.95	gold quality

Single-cell (SCXA)

Detected in 22 experiment(s), a significant marker in 17.

Experiment	Marker?	Max mean expression
E-MTAB-8495	yes	7140.49
E-MTAB-10885	yes	5320.30
E-HCAD-29	yes	3511.17
E-HCAD-4	yes	3131.64
E-MTAB-6108	yes	2626.23
E-MTAB-8207	yes	1461.66
E-MTAB-10287	yes	61.16
E-HCAD-6	yes	56.38
E-HCAD-1	yes	43.43
E-CURD-122	yes	41.56
E-CURD-46	yes	26.04
E-HCAD-10	yes	13.69
E-MTAB-8410	yes	13.69
E-CURD-119	yes	11.59
E-GEOD-130148	yes	11.23

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, EGR1, ESR2, JUNB, MAF, NCOA3, NFKB, NR1I2, PPARD, RNF2, SP1, SP3, TAL1, TFAP2A, TP53, YY1

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 30.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• the mechanical stability of ubiquitin is linkage dependent (PMID:12923571)
• These results indicate that the use of cellular promoters such as those for EF-1alpha and ubiquitin C might direct prolonged gene expression in hematopoietic and mesenchymal progenitor cells. (PMID:15893736)
• The presence of ubiquitin mainly in the nuclei and in the cytoplasm of BPH and prostatic adenocarcinoma, respectively, may suggest a role of ubiquitin in the development of the above mentioned conditions (PMID:16892003)
• Werner helicase-interacting protein 1 binds polyubiquitin via its zinc finger domain (PMID:17550899)
• Ubiquitin expression increased with increasing severity of coronary artery disease, suggesting that ubiquitin may play a critical role in the development and progression of this disease. (PMID:19094431)
• The positive rates of ubiquitin and cul-1 were significantly higher in lung cancer than those in benign lesion tissues of the lung. (PMID:19349673)
• provide insights into the pivotal role of Sp1/Sp3 binding to the intronic enhancer in the regulation of UbC transcription. (PMID:19733223)
• The structure of UbcH8 does not undergo a significant conformational change upon forming a complex with ubiquitin. (PMID:19928833)
• Studies indicate that indicating that the inhibition of the ubiquitin-proteasome system could be used as a novel approach for cancer therapy. (PMID:20491623)
• Ubiquitin and UBE1 are upregulated in tic epilepsy. (PMID:20653130)
• CHBP is an inhibitor of the ubiquitination pathway; it deamidated Gln40 in ubiquitin and ubiquitin-like protein NEDD8 in vitro and during Burkholderia infection; Cif deamidated NEDD8, abolishing activity of neddylated Cullin-RING ubiquitin ligases (PMID:20688984)
• Studies indicate that the involvement of the degradation-linked K48-ubiquitin signal and the proteasome at the sites of DSBs. (PMID:21536036)
• Studies indicate that Ubiquitin- and SUMO-mediated modification pathways have emerged as key players in regulating damage-induced template switching. (PMID:21539841)
• Studies indicate that signaling controlled by ubiquitin or ubiquitin-like proteins has recently emerged as key regulator of the cellular DNA damage response, and viruses can reveal key convergence points in this important cellular pathway. (PMID:21549706)
• Studies indicate that monoubiquitylation of PCNA allows mutagenic translesion synthesis by damage-tolerant DNA polymerases, polyubiquitylation is required mainly for an error-free pathway that likely involves template switching. (PMID:21605556)
• Studies indicate that Mdm2 has the ability to catalyze both mono- and poly-ubiquitination of p53. (PMID:21624367)
• Studies indicate that Ku80 is removed from DNA through a ubiquitin-mediated process. (PMID:21640108)
• Studies indicate that Non-proteolytic ubiquitylation of chromatin surrounding DSBs, mediated by the RNF8/RNF168 ubiquitin ligase cascade, has emerged as a key mechanism for restoration of genome integrity. (PMID:21664912)
• Studies indicate that All the Y-family polymerases have ubiquitin binding domains that bind to mono-ubiquitinated PCNA to effect the switching from replicative to Y-family polymerase. (PMID:21704031)
• The human ubiquitin C promoter transgene might be useful to selectively target projections of brain neurons. (PMID:21802467)
• Studies suggest that DNA damage-induced ubiquitination or sumoylation of PCNA prevents CRL4Cdt2-dependent degradation by inhibiting binding of Cdt1 to PCNA. (PMID:21846465)
• Ubiquitin targeting of tau protein occurs at neurofibrillary tangles in the early and intermediate maturation stages. (PMID:21919991)
• the ubiquitin independent degradation pathway utilized by a hepatitis B virus envelope protein limits antigen presentation (PMID:21969857)
• Data indicate that modification of NEMO with linear di-ubiquitin is sufficient for full NF-kappaB activation. (PMID:22605335)
• analysis of cold-induced changes in the protein ubiquitin (PMID:22737208)
• The GP78 CUE domain functions to both facilitate substrate binding and enable switching between adjacent ubiquitin molecules of a growing chain to enable processivity in ubiquitination. (PMID:23123110)
• Ubiquitin’s regulatory mechanisms of expression in heart failure patients’ cardiomyocytes. (review) (PMID:23180530)
• Regulation of ubiquitin transfer by XIAP, a dimeric RING E3 ligase. (PMID:23259674)
• Data indicate that pressure induced ubiquitin unfolding in methanol. (PMID:23284170)
• Data suggest that ubiquitin (Ub) binding provides a negative feedback loop upon NOD1 and NOD2 (nucleotide-binding oligomerization domain-containing proteins)-dependent activation of receptor-interacting protein kinase 2 (RIP2). (PMID:23300079)
• This article reviews the recent advances in proteomics of HMG20 and reveals novel networks and associations with human disease.[review] (PMID:23339974)
• The donor ubiquitin, transferred from the E2, is bound to the Nedd4 C lobe with its C-terminal tail locked in an extended conformation, primed for catalysis. (PMID:23644597)
• Yin Yang 1 intronic binding sequences and splicing elicit intron-mediated enhancement of ubiquitin C gene expression. (PMID:23776572)
• These results reveal an unanticipated mode of Ube2g2 self-association that allows Ube2g2 to effectively engage two ubiquitins to specifically synthesize Lys48-linked ubiquitin chains. (PMID:24366945)
• UbcH5c~Ubiqitin binding stabilizes an active conformation of the Shigella flexneri OspG kinase, greatly enhancing its activity. (PMID:24446487)
• Static HMG-20 structure is derived from high precision residual dipolar couplings measured in a drug-based liquid crystalline phase using NMR spectroscopy. (PMID:24568736)
• Data indicate that a single point deletion (DeltaE81) in RAP80 abrogates multivalent interactions with polyubiquitin. (PMID:24627472)
• This study identifies altered proteolysis as a feature of persistent podocyte injury. In the future, specific UPS proteins may serve as new biomarkers or therapeutic targets in persistent nephrotic syndrome. (PMID:24722446)
• Data indicate that conditional replacement of endogenous ubiquitin (Ub) by Ub(R54A/Y59A) or Ub(K48R) yielded profound apoptosis at a similar extent. (PMID:24912152)
• Studies indicate that ubiquitin proteasome system (UPS) controls all aspects of cholesterol metabolism including its synthesis, uptake, and efflux. (PMID:25220377)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ubc	ENSDARG00000102632
mus_musculus	Ubc	ENSMUSG00000008348
rattus_norvegicus	Ubc	ENSRNOG00000057823
drosophila_melanogaster	Ubi-p63E	FBGN0003943
drosophila_melanogaster	Ubi-p5E	FBGN0086558
caenorhabditis_elegans		WBGENE00006727

Paralogs (10): UBL4A (ENSG00000102178), NEDD8 (ENSG00000129559), RPS27A (ENSG00000143947), UBB (ENSG00000170315), ZFAND4 (ENSG00000172671), UBL4B (ENSG00000186150), ISG15 (ENSG00000187608), ANKUB1 (ENSG00000206199), UBD (ENSG00000213886), UBA52 (ENSG00000221983)

Protein

Protein identifiers

Polyubiquitin-C — P0CG48 (reviewed: P0CG48)

All UniProt accessions (10): P0CG48, F5GXK7, F5GYU3, F5GZ39, F5H265, F5H2Z3, F5H388, F5H6Q2, F5H747, Q96C32

UniProt curated annotations — full annotation on UniProt →

Function. Exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in proteotoxic stress response and cell cycle; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling. During ubiquitination, the acceptor ubiquitin is positioned in the active site via direct interaction with the E2 ubiquitin-conjugating enzymes such as UBE2R2. As a monoubiquitin, its C-terminal glycine is recognized as a C-degron by Cul2-RING (CRL2) E3 ubiquitin-protein ligase complexes.

Subcellular location. Cytoplasm. Nucleus. Mitochondrion outer membrane.

Post-translational modifications. Phosphorylated at Ser-65 by PINK1 during mitophagy. Phosphorylated ubiquitin specifically binds and activates parkin (PRKN), triggering mitophagy. Phosphorylation does not affect E1-mediated E2 charging of ubiquitin but affects discharging of E2 enzymes to form polyubiquitin chains. It also affects deubiquitination by deubiquitinase enzymes such as USP30. Mono-ADP-ribosylated at the C-terminus by PARP9, a component of the PPAR9-DTX3L complex. ADP-ribosylation requires processing by E1 and E2 enzymes and prevents ubiquitin conjugation to substrates such as histones. (Microbial infection) Mono-ADP-ribosylated at Thr-66 by the C.violaceum CteC virulence factor. ADP-ribosylation causes the shutdown of polyubiquitin synthesis and disrupts the recognition and reversal of polyubiquitin.

Miscellaneous. Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins eL40 and eS31, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains. For the sake of clarity sequence features are annotated only for the first chain, and are not repeated for each of the following chains.

Similarity. Belongs to the ubiquitin family.

RefSeq proteins (1): NP_066289* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000626	Ubiquitin-like_dom	Domain
IPR019954	Ubiquitin_CS	Conserved_site
IPR019956	Ubiquitin_dom	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR050158	Ubiquitin_ubiquitin-like	Family

Pfam: PF00240

UniProt features (97 total): strand 26, mutagenesis site 22, helix 11, chain 9, domain 9, cross-link 8, site 3, modified residue 3, turn 3, sequence conflict 2, propeptide 1

Structure

Experimental structures (PDB)

353 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6Q00	X-RAY DIFFRACTION	0.85
1OGW	X-RAY DIFFRACTION	1.32
5NL4	X-RAY DIFFRACTION	1.32
2GBJ	X-RAY DIFFRACTION	1.35
4HK2	X-RAY DIFFRACTION	1.4
9FJ3	X-RAY DIFFRACTION	1.4
8ST7	X-RAY DIFFRACTION	1.44
1XD3	X-RAY DIFFRACTION	1.45
4IUM	X-RAY DIFFRACTION	1.45
7UV5	X-RAY DIFFRACTION	1.45
5NLF	X-RAY DIFFRACTION	1.5
9F6G	X-RAY DIFFRACTION	1.5
9OVX	X-RAY DIFFRACTION	1.5
4UN2	X-RAY DIFFRACTION	1.51
4V3L	X-RAY DIFFRACTION	1.53
5NLI	X-RAY DIFFRACTION	1.53
9FJ4	X-RAY DIFFRACTION	1.54
2GBM	X-RAY DIFFRACTION	1.55
3BY4	X-RAY DIFFRACTION	1.55
2GBN	X-RAY DIFFRACTION	1.6
2ZCB	X-RAY DIFFRACTION	1.6
5OXH	X-RAY DIFFRACTION	1.6
5OXI	X-RAY DIFFRACTION	1.63
4K1R	X-RAY DIFFRACTION	1.63
5AF5	X-RAY DIFFRACTION	1.68
3VUX	X-RAY DIFFRACTION	1.7
3V6C	X-RAY DIFFRACTION	1.7
5NMC	X-RAY DIFFRACTION	1.7
6B7M	X-RAY DIFFRACTION	1.7
8E7O	X-RAY DIFFRACTION	1.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P0CG48-F1	88.99	0.58

Antibody-complex structures (SAbDab): 5 — 3DVG, 3DVN, 3U30, 6EQI, 7KEO

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 (3): 54 (interacts with activating enzyme); 68 (essential for function); 72 (interacts with activating enzyme)

Post-translational modifications (11): 65, 66, 76, 6, 11, 27, 29, 33, 48, 63, 76

Mutagenesis-validated functional residues (22):

Position	Phenotype
7	impairs ubiquitination by crl2(klhdc3) e3 ligase complex; when associated with d-9.
9	impairs ubiquitination by crl2(klhdc3) e3 ligase complex; when associated with d-7.
42	impairs ubiquitination by crl2(klhdc3) e3 ligase complex; when associated with d-44. impairs ubiquitination by crl2(klhd
44	impairs ubiquitination by crl2(klhdc3) e3 ligase complex; when associated with e-42. impairs ubiquitination by crl2(klhd
48	no effect on hltf-mediated polyubiquitination of pcna. impairs ubiquitination by crl2(klhdc3) e3 ligase complex.
54	decreases affinity for ube2r2 in crl2(fem1c)-ube2r2 complex.
60	decreases affinity for ube2r2 in crl2(fem1c)-ube2r2 complex.
63	abolishes hltf-mediated polyubiquitination of pcna.
65	prevents phosphorylation in case of mitophagy. decreased localization of prkn to mitochondria.
65	phosphomimetic mutant that binds and activates prkn.
66	abolishes ctec-catalyzed adp-ribosylation.
68	decreases affinity for ube2r2 in ecs(fem1c)-ube2r2 complex. impairs ubiquitination by crl2(klhdc3) e3 ligase complex; wh
68	loss of dtx3l-mediated polyubiquitination of histone h3 and h4.
72	impairs ubiquitination by crl2(klhdc3) e3 ligase complex; when associated with e-42. impairs ubiquitination by crl2(klhd
72	no effect on adp-ribosylation.
72	no effect on adp-ribosylation, when associated with k-74.
74	no effect on adp-ribosylation.
74	no effect on adp-ribosylation, when associated with k-72.
75	no effect on ubiquitination by crl2(klhdc3) e3 ligase complex. impairs ubiquitination by crl2(klhdc10) e3 ligase complex
76	loss of adp-ribosylation. impairs ubiquitination by crl2(klhdc3) e3 ligase complex. no effect on ubiquitination by crl2(
76	impairs ubiquitination by crl2(klhdc3) and crl2(klhdc10) e3 ligase complex.

Function

Pathways and Gene Ontology

Reactome pathways

201 pathways

ID	Pathway
R-HSA-110312	Translesion synthesis by REV1
R-HSA-110314	Recognition of DNA damage by PCNA-containing replication complex
R-HSA-110320	Translesion Synthesis by POLH
R-HSA-1169091	Activation of NF-kappaB in B cells
R-HSA-1169408	ISG15 antiviral mechanism
R-HSA-1234176	Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha
R-HSA-1236382	Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants
R-HSA-1236974	ER-Phagosome pathway
R-HSA-1253288	Downregulation of ERBB4 signaling
R-HSA-1295596	Spry regulation of FGF signaling
R-HSA-1358803	Downregulation of ERBB2:ERBB3 signaling
R-HSA-162588	Budding and maturation of HIV virion
R-HSA-168638	NOD1/2 Signaling Pathway
R-HSA-168927	TICAM1, RIP1-mediated IKK complex recruitment
R-HSA-168928	DDX58/IFIH1-mediated induction of interferon-alpha/beta
R-HSA-174048	APC/C:Cdc20 mediated degradation of Cyclin B
R-HSA-174084	Autodegradation of Cdh1 by Cdh1:APC/C
R-HSA-174113	SCF-beta-TrCP mediated degradation of Emi1
R-HSA-174154	APC/C:Cdc20 mediated degradation of Securin
R-HSA-174178	APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1
R-HSA-174184	Cdc20:Phospho-APC/C mediated degradation of Cyclin A
R-HSA-174490	Membrane binding and targetting of GAG proteins
R-HSA-175474	Assembly Of The HIV Virion
R-HSA-179409	APC-Cdc20 mediated degradation of Nek2A
R-HSA-180534	Vpu mediated degradation of CD4
R-HSA-180585	Vif-mediated degradation of APOBEC3G
R-HSA-182971	EGFR downregulation
R-HSA-187577	SCF(Skp2)-mediated degradation of p27/p21
R-HSA-195253	Degradation of beta-catenin by the destruction complex
R-HSA-201681	TCF dependent signaling in response to WNT

MSigDB gene sets: 617 (showing top): REACTOME_TRAF6_MEDIATED_INDUCTION_OF_TAK1_COMPLEX_WITHIN_TLR4_COMPLEX, REACTOME_DDX58_IFIH1_MEDIATED_INDUCTION_OF_INTERFERON_ALPHA_BETA, REACTOME_IKK_COMPLEX_RECRUITMENT_MEDIATED_BY_RIP1, REACTOME_FORMATION_OF_INCISION_COMPLEX_IN_GG_NER, REACTOME_ENDOSOMAL_SORTING_COMPLEX_REQUIRED_FOR_TRANSPORT_ESCRT, REACTOME_DNA_REPLICATION, REACTOME_SIGNALING_BY_NOTCH, REACTOME_APC_C_CDH1_MEDIATED_DEGRADATION_OF_CDC20_AND_OTHER_APC_C_CDH1_TARGETED_PROTEINS_IN_LATE_MITOSIS_EARLY_G1, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_APC_C_CDC20_MEDIATED_DEGRADATION_OF_CYCLIN_B, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, YAGI_AML_WITH_INV_16_TRANSLOCATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_NOD1_2_SIGNALING_PATHWAY, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM

GO Biological Process (2): protein ubiquitination (GO:0016567), modification-dependent protein catabolic process (GO:0019941)

GO Molecular Function (5): RNA binding (GO:0003723), protein tag activity (GO:0031386), ubiquitin protein ligase binding (GO:0031625), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (14): obsolete extracellular space (GO:0005615), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrial outer membrane (GO:0005741), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), plasma membrane (GO:0005886), endosome membrane (GO:0010008), endocytic vesicle membrane (GO:0030666), vesicle (GO:0031982), extracellular exosome (GO:0070062), mitochondrion (GO:0005739), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-20 pathways:

Category	Pathways
Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template	2
APC/C:Cdc20 mediated degradation of mitotic proteins	2
APC/C-mediated degradation of cell cycle proteins	2
DNA Damage Bypass	1
Downstream signaling events of B Cell Receptor (BCR)	1
Antimicrobial mechanism of IFN-stimulated genes	1
Cellular response to hypoxia	1
Signaling by Ligand-Responsive EGFR Variants in Cancer	1
Antigen processing-Cross presentation	1
Signaling by ERBB4	1
Negative regulation of FGFR1 signaling	1
Negative regulation of FGFR2 signaling	1
Negative regulation of FGFR3 signaling	1
Negative regulation of FGFR4 signaling	1
Downregulation of ERBB2 signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
intracellular membrane-bounded organelle	2
cytoplasm	2
cytoplasmic vesicle membrane	2
bounding membrane of organelle	2
protein modification by small protein conjugation	1
protein catabolic process	1
protein modification process	1
modification-dependent macromolecule catabolic process	1
nucleic acid binding	1
molecular tag activity	1
ubiquitin-like protein ligase binding	1
binding	1
cation binding	1
nuclear lumen	1
intracellular anatomical structure	1
mitochondrial membrane	1
organelle outer membrane	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
endosome	1
endocytic vesicle	1
membrane-bounded organelle	1
extracellular vesicle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

499 interactions, top by confidence:

A	B	Type	Score
PSMD4	UBC	psi-mi:“MI:0407”(direct interaction)	0.850
UBC	SQSTM1	psi-mi:“MI:0407”(direct interaction)	0.810
UBC	RELA	psi-mi:“MI:0915”(physical association)	0.770
UBC	IKBKG	psi-mi:“MI:0407”(direct interaction)	0.750
MAP3K7	UBC	psi-mi:“MI:0915”(physical association)	0.740
UBC	TAX1BP1	psi-mi:“MI:0915”(physical association)	0.710
MYC	UBC	psi-mi:“MI:0915”(physical association)	0.690
RAD23B	UBC	psi-mi:“MI:0407”(direct interaction)	0.680
UBC	RAD23B	psi-mi:“MI:0915”(physical association)	0.680
UBC	UBAC1	psi-mi:“MI:0915”(physical association)	0.670
UBC	DENR	psi-mi:“MI:0915”(physical association)	0.660
UBC	NBR1	psi-mi:“MI:0915”(physical association)	0.640
USP4	PRPF3	psi-mi:“MI:0914”(association)	0.640
NBR1	UBC	psi-mi:“MI:0407”(direct interaction)	0.640
NBR1	UBC	psi-mi:“MI:0403”(colocalization)	0.640
ADRM1	UBC	psi-mi:“MI:0915”(physical association)	0.610
UBC	DAZAP2	psi-mi:“MI:0915”(physical association)	0.560
UBC	UBQLN2	psi-mi:“MI:0915”(physical association)	0.560
UBC	PLSCR4	psi-mi:“MI:0915”(physical association)	0.560
UBC	YOD1	psi-mi:“MI:0915”(physical association)	0.560
UBC	DESI1	psi-mi:“MI:0915”(physical association)	0.560
EPN2	UBC	psi-mi:“MI:0915”(physical association)	0.560
UBC	CDIP1	psi-mi:“MI:0915”(physical association)	0.560
UBC	PLEKHB2	psi-mi:“MI:0915”(physical association)	0.560
UBC	FAM168A	psi-mi:“MI:0915”(physical association)	0.560
UBC	MTURN	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (4546): UBC (Reconstituted Complex), UBC (Biochemical Activity), UBC (Biochemical Activity), UBC (Biochemical Activity), UBC (Co-crystal Structure), UBC (Reconstituted Complex), UBC (Co-localization), UBC (Affinity Capture-Western), UBC (Affinity Capture-MS), UBC (Reconstituted Complex), UBC (Co-crystal Structure), UBC (Affinity Capture-MS), UBC (Affinity Capture-MS), UBC (Affinity Capture-MS), UBC (Reconstituted Complex)

ESM2 similar proteins: A0A0H2URK1, A0A0H3HIJ5, A0A1D8PQ86, A1C3L3, A8AWU7, O86487, P05227, P08519, P08640, P0C727, P0C728, P0CG48, P0CG50, P0CG61, P0CG64, P0CG66, P0CG69, P0CG71, P0CH28, P12027, P13821, P15941, P19837, P24856, P32768, P39712, P46804, P62976, Q02192, Q27905, Q2FJ79, Q2G0L5, Q41406, Q49537, Q49538, Q4L9P0, Q54GV8, Q59SG9, Q5HIB4, Q5SSG8

Diamond homologs: A3KPW9, A4IH17, A5D9M6, A7X5R6, C4YP88, D5LXJ0, P05759, P0C016, P0C224, P0C8R3, P0CG47, P0CG48, P0CG49, P0CG50, P0CG51, P0CG53, P0CG54, P0CG55, P0CG60, P0CG61, P0CG62, P0CG63, P0CG64, P0CG65, P0CG66, P0CG67, P0CG68, P0CG69, P0CG70, P0CG71, P0CG72, P0CG73, P0CG74, P0CG75, P0CG76, P0CG77, P0CG78, P0CG79, P0CG80, P0CG81

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
PINK1	“up-regulates activity”	UBC	phosphorylation
UBC	“up-regulates activity”	PRKN	binding
UCHL1	“up-regulates quantity”	UBC	cleavage
OTULIN	“up-regulates quantity”	UBC	cleavage
USP5	“up-regulates quantity”	UBC	cleavage

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 136 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
TNFR1-induced NF-kappa-B signaling pathway	11	38.1×	2e-12
MAP3K8 (TPL2)-dependent MAPK1/3 activation	5	36.8×	7e-06
NOD1/2 Signaling Pathway	9	29.4×	4e-09
TNFR1-induced proapoptotic signaling	6	27.2×	4e-06
TCR signaling	5	25.6×	4e-05
Regulation of TNFR1 signaling	10	23.1×	4e-09
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	6	22.1×	9e-06
TNF signaling	5	21.8×	7e-05

GO biological processes:

GO term	Partners	Fold	FDR
protein K63-linked deubiquitination	5	25.4×	2e-04
receptor internalization	7	18.4×	2e-05
positive regulation of cell cycle	5	18.0×	7e-04
canonical NF-kappaB signal transduction	5	14.9×	2e-03
protein destabilization	6	14.2×	5e-04
protein deubiquitination	9	13.0×	1e-05
macroautophagy	6	11.7×	1e-03
negative regulation of protein ubiquitination	5	11.6×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	21
Likely benign	36
Benign	4

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
4532272	GRCh37/hg19 12q24.22-24.33(chr12:117533207-133777902)x3	Likely pathogenic

SpliceAI

341 predictions. Top by Δscore:

Variant	Effect	Δscore
12:124913771:TTGT:T	acceptor_gain	1.0000
12:124913772:TGT:T	acceptor_gain	1.0000
12:124913773:GT:G	acceptor_gain	1.0000
12:124913773:GTC:G	acceptor_loss	1.0000
12:124913775:C:CC	acceptor_gain	1.0000
12:124913775:CT:C	acceptor_loss	1.0000
12:124914583:TCACC:T	donor_loss	1.0000
12:124914584:CACC:C	donor_loss	1.0000
12:124914585:A:AC	donor_gain	1.0000
12:124914585:A:AT	donor_loss	1.0000
12:124914586:C:CC	donor_gain	1.0000
12:124914586:C:G	donor_loss	1.0000
12:124914586:CCAA:C	donor_gain	1.0000
12:124913770:ATTGT:A	acceptor_gain	0.9900
12:124913779:C:CT	acceptor_gain	0.9900
12:124913780:A:T	acceptor_gain	0.9900
12:124914579:CTACT:C	donor_loss	0.9900
12:124914585:AC:A	donor_gain	0.9900
12:124914586:CC:C	donor_gain	0.9900
12:124914586:CCA:C	donor_gain	0.9900
12:124914586:CCAAG:C	donor_gain	0.9900
12:124914868:T:TA	donor_gain	0.9900
12:124915247:C:A	donor_gain	0.9900
12:124914581:ACT:A	donor_loss	0.9800
12:124915222:T:TA	donor_gain	0.9800
12:124915232:AGCCC:A	donor_gain	0.9800
12:124915246:T:TA	donor_gain	0.9700
12:124914672:T:TA	donor_gain	0.9600
12:124914850:A:AC	donor_gain	0.9400
12:124915164:AC:A	donor_gain	0.9400

AlphaMissense

4519 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:124912198:A:G	L525P	1.000
12:124912426:A:G	L449P	1.000
12:124912497:A:C	F425L	1.000
12:124912497:A:T	F425L	1.000
12:124912499:A:G	F425L	1.000
12:124912504:A:G	L423S	1.000
12:124912654:A:G	L373P	1.000
12:124912732:A:C	L347W	1.000
12:124912732:A:G	L347S	1.000
12:124912882:A:G	L297P	1.000
12:124913110:A:G	L221P	1.000
12:124913338:A:G	L145P	1.000
12:124913416:A:G	L119S	1.000
12:124911970:A:G	L145P	0.999
12:124912048:A:G	L119S	0.999
12:124912204:A:G	L523P	0.999
12:124912255:A:G	L506P	0.999
12:124912269:A:C	F501L	0.999
12:124912269:A:T	F501L	0.999
12:124912271:A:G	F501L	0.999
12:124912276:A:C	L499W	0.999
12:124912276:A:G	L499S	0.999
12:124912281:C:A	Q497H	0.999
12:124912281:C:G	Q497H	0.999
12:124912392:G:C	F460L	0.999
12:124912392:G:T	F460L	0.999
12:124912394:A:G	F460L	0.999
12:124912426:A:T	L449Q	0.999
12:124912432:A:G	L447P	0.999
12:124912432:A:T	L447Q	0.999

dbSNP variants (sampled 300 via entrez): RS1000208526 (12:124911661 C>A,G,T), RS1000263784 (12:124916004 C>G,T), RS1000340405 (12:124915676 G>A), RS1000601663 (12:124911575 C>A,T), RS1001268579 (12:124915001 G>A,C,T), RS1002329979 (12:124914412 A>G), RS1002551196 (12:124913855 G>A,T), RS1002805359 (12:124914776 C>A,G), RS1003216474 (12:124913951 T>C), RS1004303717 (12:124916114 C>T), RS1004341787 (12:124912555 A>C), RS1004483861 (12:124914129 G>A,C), RS1005278390 (12:124911164 C>G,T), RS1005670465 (12:124915140 C>T), RS1005911307 (12:124914537 C>G,T)

Disease associations

OMIM: gene MIM:191340 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): intellectual disability (MONDO:0001071)

Orphanet (1): NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

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

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST006005_22	High density lipoprotein cholesterol levels	1.000000e-32
GCST006034_24	Total cholesterol levels	6.000000e-09
GCST008070_118	HDL cholesterol levels	3.000000e-20
GCST008070_51	HDL cholesterol levels	2.000000e-24
GCST008075_148	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	7.000000e-44
GCST008075_208	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	1.000000e-24
GCST008075_33	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	7.000000e-19
GCST008084_153	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	8.000000e-49
GCST008084_44	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	6.000000e-21
GCST008084_71	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	3.000000e-27
GCST008085_157	HDL cholesterol levels in current drinkers	4.000000e-09
GCST008085_52	HDL cholesterol levels in current drinkers	2.000000e-24
GCST008085_79	HDL cholesterol levels in current drinkers	5.000000e-17
GCST011348_34	High density lipoprotein cholesterol levels	4.000000e-40

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004574	total cholesterol measurement
EFO:0004329	alcohol drinking

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523179 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases reaction, affects binding, increases stability, increases expression, increases reaction	5
cobaltous chloride	increases expression	3
Cadmium Chloride	increases palmitoylation, increases expression, decreases reaction, increases abundance	3
moringin	affects cotreatment, increases expression	2
Arsenic	affects cotreatment, increases abundance, increases expression	2
Cannabidiol	decreases expression, affects cotreatment, increases expression	2
Dronabinol	decreases expression	2
Tobacco Smoke Pollution	increases expression	2
Cyclosporine	increases expression, increases methylation	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
glycidyl methacrylate	decreases expression	1
lead acetate	increases expression	1
sodium arsenate	increases abundance, increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
5-hydroxymethylcytosine	increases abundance, increases expression	1
2-butenal	increases expression	1
beta-lapachone	increases expression	1
2,6-dichloro-4-nitrophenol	increases expression	1
sodium bichromate	increases expression	1
nickel subsulfide	increases expression	1
2-bromopalmitate	increases abundance, increases palmitoylation, decreases reaction	1
imidazopyrazole	increases expression	1
ferrous chloride	increases expression	1
cupric chloride	increases expression	1
cadmium sulfate	increases expression	1
beta-methylcholine	affects expression	1
arsenic trichloride	affects cotreatment, increases abundance, increases expression	1
dinophysistoxin 1	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4341431	Binding	Binding affinity to UBC in human A549 cells lysates grown on SILAC media at 10 uM incubated for 1 hr by LC-MS/MS analysis relative to untreated control	Profiling withanolide A for therapeutic targets in neurodegenerative diseases. — Bioorg Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders