UBB

Summary

UBB (ubiquitin B, HGNC:12463) is a protein-coding gene on chromosome 17p11.2, encoding Polyubiquitin-B (P0CG47). Exists either covalently attached to another protein, or free (unanchored). It is a selective cancer dependency (DepMap: 13.6% of cell lines).

This gene encodes ubiquitin, one of the most conserved proteins known. Ubiquitin has a major role in targeting cellular proteins for degradation by the 26S proteosome. It is also involved in the maintenance of chromatin structure, the regulation of gene expression, and the stress response. Ubiquitin is synthesized as a precursor protein consisting of either polyubiquitin chains or a single ubiquitin moiety fused to an unrelated protein. This gene consists of three direct repeats of the ubiquitin coding sequence with no spacer sequence. Consequently, the protein is expressed as a polyubiquitin precursor with a final amino acid after the last repeat. An aberrant form of this protein has been detected in patients with Alzheimer’s disease and Down syndrome. Pseudogenes of this gene are located on chromosomes 1, 2, 13, and 17. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 7314 — RefSeq curated summary.

At a glance

• Gene–disease (curated): isolated cleft palate (No Known Disease Relationship, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 21 total
• Phenotypes (HPO): 23
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 13.6% of screened cell lines
• MANE Select transcript: NM_018955

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12463
Approved symbol	UBB
Name	ubiquitin B
Location	17p11.2
Locus type	gene with protein product
Status	Approved
Aliases	MGC8385, FLJ25987
Ensembl gene	ENSG00000170315
Ensembl biotype	protein_coding
OMIM	191339
Entrez	7314

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 17 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000302182, ENST00000395837, ENST00000395839, ENST00000535788, ENST00000577640, ENST00000577958, ENST00000578649, ENST00000578706, ENST00000614404, ENST00000879806, ENST00000879807, ENST00000879808, ENST00000879809, ENST00000879810, ENST00000879811, ENST00000879812, ENST00000915770, ENST00000915771

RefSeq mRNA: 6 — MANE Select: NM_018955 NM_001281716, NM_001281717, NM_001281718, NM_001281719, NM_001281720, NM_018955

CCDS: CCDS11177

Canonical transcript exons

ENST00000302182 — 2 exons

Exon	Start	End
ENSE00001548574	16381902	16382740
ENSE00002254413	16381091	16381184

Expression profiles

Bgee: expression breadth ubiquitous, 305 present calls, max score 100.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 347.0769 / max 14125.9882, expressed in 1821 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
159690	336.8245	1821
159692	6.4543	1225
159688	0.9733	556
159691	0.8156	351
159687	0.7662	412
159695	0.6750	380
159693	0.1759	62
159689	0.1657	32
159685	0.0994	21
159686	0.0638	18

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pons	UBERON:0000988	100.00	gold quality
adult organism	UBERON:0007023	100.00	gold quality
endothelial cell	CL:0000115	99.99	gold quality
substantia nigra pars compacta	UBERON:0001965	99.99	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.99	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.99	gold quality
pancreatic ductal cell	CL:0002079	99.98	gold quality
bronchial epithelial cell	CL:0002328	99.98	gold quality
lateral globus pallidus	UBERON:0002476	99.98	gold quality
middle temporal gyrus	UBERON:0002771	99.98	gold quality
pigmented layer of retina	UBERON:0001782	99.97	gold quality
subthalamic nucleus	UBERON:0001906	99.97	gold quality
trabecular bone tissue	UBERON:0002483	99.97	gold quality
superior vestibular nucleus	UBERON:0007227	99.97	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.97	gold quality
oocyte	CL:0000023	99.96	gold quality
secondary oocyte	CL:0000655	99.96	gold quality
renal glomerulus	UBERON:0000074	99.96	gold quality
nephron tubule	UBERON:0001231	99.96	gold quality
parotid gland	UBERON:0001831	99.96	gold quality
medulla oblongata	UBERON:0001896	99.96	gold quality
dorsal plus ventral thalamus	UBERON:0001897	99.96	gold quality
epithelium of bronchus	UBERON:0002031	99.96	gold quality
inferior olivary complex	UBERON:0002127	99.96	gold quality
bronchus	UBERON:0002185	99.96	gold quality
ventral tegmental area	UBERON:0002691	99.96	gold quality
CA1 field of hippocampus	UBERON:0003881	99.96	gold quality
metanephric glomerulus	UBERON:0004736	99.96	gold quality
kidney epithelium	UBERON:0004819	99.96	gold quality
inferior vagus X ganglion	UBERON:0005363	99.96	gold quality

Single-cell (SCXA)

Detected in 30 experiment(s), a significant marker in 14.

Experiment	Marker?	Max mean expression
E-MTAB-9221	yes	6212.71
E-GEOD-134144	yes	4189.26
E-GEOD-150728	yes	3457.75
E-GEOD-84465	yes	3362.03
E-MTAB-8207	yes	2340.83
E-HCAD-4	yes	169.53
E-HCAD-1	yes	104.29
E-CURD-88	yes	40.52
E-MTAB-10553	yes	30.57
E-MTAB-8142	yes	17.57
E-GEOD-135922	yes	16.98
E-MTAB-8410	yes	10.63
E-HCAD-9	yes	10.48
E-MTAB-9801	yes	6.20
E-MTAB-10137	no	4077.44

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HSF1

miRNA regulators (miRDB)

9 targeting UBB, 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-3143	99.93	71.96	3104
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-4671-3P	99.88	72.46	1045
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-12132	99.47	68.90	1341
HSA-MIR-4260	98.78	65.37	848
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-891A-5P	93.24	65.86	104

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 13.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 33)

• Molecular misreading of the ubiquitin B gene and hepatic mallory body formation. (PMID:12055595)
• expression of UBB+1 causes proteasome inhibition and induces expression of heat-shock proteins; although UBB+1-expressing cells have a compromised ubiquitin-proteasome system, they are protected against oxidative stress (PMID:12871580)
• The temporal localization of frame-shift ubiquitin-B and amyloid precursor protein, and complement proteins in the brain of non-demented control patients with increasing Alzheimer’s disease pathology. (PMID:12893422)
• In sporadic inclusion-body myositis, UBB+1 may be pathogenic by inhibiting proteasome, thereby promoting accumulation of cytotoxic misfolded amyloid-beta and phosphorylated-tau. (PMID:15452314)
• UBB+1, a mutant form of ubiquitin was present in the majority of NFTs, whereas co-existence of alpha-synuclein and UBB+1 was found in only a few neurons in cases of combined multiple system atrophy and Alzheimer’s disease. (PMID:17237936)
• K63-polyubiquitination guards against chemical carcinogenesis by preventing mutagenesis and thus contributing to genomic stability (PMID:17395554)
• UBB(+1), at low expression levels, is efficiently degraded by the proteasome, but at high levels, the proteasome failed to degrade UBB(+1), causing its accumulation. (PMID:17405812)
• analyse the expression of mutant ubiquitin (UBB+1), in muscle biopsies from patients suffering from myotilinopathy and desminopathy (PMID:17931355)
• The expression a mutant human UBB analogous (UB14) in yeast markedly enhanced cellular susceptibility to toxic protein aggregates. (PMID:19214209)
• Studies indicate that indicating that the inhibition of the ubiquitin-proteasome system could be used as a novel approach for cancer therapy. (PMID:20491623)
• Results suggest that the interaction between E2-25K and UBB(+1) is critical for the synthesis and accumulation of UBB(+1)-anchored polyubiquitin, which results in proteasomal inhibition and neuronal cell death. (PMID:20826778)
• The results of this study demonstrated that the UBB mutation caused the subtle defect in spatial reference memory formation, caused by a decrease in forebrain proteasome activity. (PMID:21059367)
• analysis of orexin receptor 1 and 2 -arrestin-ubiquitin complexes (PMID:21378163)
• Studies indicate that DUBs recycle ubiquitin by processing polyubiquitin chains to generate free ubiquitin, and can be regulated by ubiquitination or phosphorylation. (PMID:21480003)
• Studies indicate that biomedical research on ubiquitin moves into translational research and drug discovery. (PMID:21544573)
• age-dependent accumulation of Ubb(+1) , and how Ubb(+1) -mediated proteasome inhibition may contribute to Alzheimer’s disease. [review] (PMID:22082077)
• A significant decrease in amyloid beta deposition and plaque formation suggests a role for the ubiquitin-proteasome system in the amyloid pathology of Alzheimer’s disease. (PMID:22797007)
• downregulation of ubiquitin through Ubb-KD is a potential anti-cancer treatment by inhibiting ubiquitination at multiple sites related to oncogenic pathways and by weakening the ability of cancer cells to overcome increased stress. (PMID:24022007)
• UbB was significantly increased in prolonged Trichostatin A-selected HeLa cells and it played a key role in the maintenance of cervical cancer stem-like cells (PMID:24367661)
• Data suggest that both human ubiquitin and HFBII (hydrophobin-II from Trichoderma reesei) exhibit a critical surface hydration level (or effective hydrophobic interface at the surface) at which percolation transition of water network occurs. (PMID:25204743)
• A new crystallographic structure of human ubiquitin solved from crystals grown in the presence of magnesium. (PMID:26750481)
• The C-terminal five residues of Ub, RLRGG, are responsible for the interaction with the Middle-East respiratory syndrome coronavirus (MERS-CoV) papain-like protease. (PMID:27245450)
• The polyubiquitinated forms of the neurodegenerative ubiquitin mutant UBB have been characterized. (PMID:27861798)
• This study demonstrated that the Deposition of mutant ubiquitin in parkinsonism-dementia complex of Guam. (PMID:29122008)
• Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin C. (PMID:29130934)
• this study shows that molecular mimicry of human ubiquitin by Bacteroides fragilis ubiquitin could be a trigger for autoimmune disease. (PMID:30076785)
• The Molecular Misreading of APP and UBB Induces a Humoral Immune Response in Alzheimer’s Disease Patients with Diagnostic Ability. (PMID:31654319)
• Simultaneous Disruption of Both Polyubiquitin Genes Affects Proteasome Function and Decreases Cellular Proliferation. (PMID:32705536)
• The Ubiquitin Gene Expression Pattern and Sensitivity to UBB and UBC Knockdown Differentiate Primary 23132/87 and Metastatic MKN45 Gastric Cancer Cells. (PMID:32751694)
• High Expression of UBB, RAC1, and ITGB1 Predicts Worse Prognosis among Nonsmoking Patients with Lung Adenocarcinoma through Bioinformatics Analysis. (PMID:33134373)
• Bioinformatics analysis of mRNA and miRNA microarray to identify the key miRNA-mRNA pairs in cisplatin-resistant ovarian cancer. (PMID:33892654)
• UBB(+1) reduces amyloid-beta cytotoxicity by activation of autophagy in yeast. (PMID:34751669)
• Downregulation of UBB potentiates SP1/VEGFA-dependent angiogenesis in clear cell renal cell carcinoma. (PMID:38467852)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	UBB	ENSDARG00000002369
mus_musculus	Ubb	ENSMUSG00000019505
rattus_norvegicus	Ubb	ENSRNOG00000066088
drosophila_melanogaster	CG11700	FBGN0029856

Paralogs (10): UBL4A (ENSG00000102178), NEDD8 (ENSG00000129559), RPS27A (ENSG00000143947), UBC (ENSG00000150991), ZFAND4 (ENSG00000172671), UBL4B (ENSG00000186150), ISG15 (ENSG00000187608), ANKUB1 (ENSG00000206199), UBD (ENSG00000213886), UBA52 (ENSG00000221983)

Protein

Protein identifiers

Polyubiquitin-B — P0CG47 (reviewed: P0CG47)

All UniProt accessions (6): P0CG47, B4DV12, J3QKN0, J3QS39, J3QSA3, Q5U5U6

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.

Subunit / interactions. Interacts with SKP1-KMD2A and SKP1-KMD2B complexes. Interacts with REV1.

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. The mRNA encoding variant UBB(+1) is produced by an unknown mechanism involving the deletion of a GT dinucleotide in the close proximity of a GAGAG motif. This variant mRNA is found in normal brain, but the encoded protein accumulates only in brain neurofibrillary tangles and neuritic plaques in Alzheimer disease and other tauopathies, as well as polyglutaminopathies. UBB(+1) variant cannot be used for polyubiquitination, is not effectively degraded by the proteasome when ubiquitinated and ubiquitinated UBB(+1) is refractory to disassembly by deubiquitinating enzymes (DUBs). In healthy brain, UBB(+1) C-terminus can be cleaved by UCHL3. For a better understanding, features related to ubiquitin are only indicated for the first chain.

Similarity. Belongs to the ubiquitin family.

RefSeq proteins (6): NP_001268645, NP_001268646, NP_001268647, NP_001268648, NP_001268649, NP_061828* (*=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 (53 total): strand 14, mutagenesis site 11, cross-link 8, helix 6, chain 3, modified residue 3, domain 3, site 3, sequence variant 1, propeptide 1

Structure

Experimental structures (PDB)

287 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5NVG	X-RAY DIFFRACTION	1.07
5TOG	X-RAY DIFFRACTION	1.08
5TOF	X-RAY DIFFRACTION	1.12
4XOF	X-RAY DIFFRACTION	1.15
5GOD	X-RAY DIFFRACTION	1.15
5GOB	X-RAY DIFFRACTION	1.15
5W46	X-RAY DIFFRACTION	1.18
7S6O	X-RAY DIFFRACTION	1.25
8IC9	X-RAY DIFFRACTION	1.25
5DK8	X-RAY DIFFRACTION	1.32
7CAP	X-RAY DIFFRACTION	1.33
5V1Y	X-RAY DIFFRACTION	1.42
5KYC	X-RAY DIFFRACTION	1.43
5KYF	X-RAY DIFFRACTION	1.45
7UV5	X-RAY DIFFRACTION	1.45
9AVT	X-RAY DIFFRACTION	1.5
5YT6	X-RAY DIFFRACTION	1.5
5NLJ	X-RAY DIFFRACTION	1.53
4ZPZ	X-RAY DIFFRACTION	1.54
5GOJ	X-RAY DIFFRACTION	1.55
5K9P	X-RAY DIFFRACTION	1.55
7NBB	X-RAY DIFFRACTION	1.55
7AI0	X-RAY DIFFRACTION	1.56
5O6T	X-RAY DIFFRACTION	1.57
5GOI	X-RAY DIFFRACTION	1.59
6FDK	X-RAY DIFFRACTION	1.6
5KYD	X-RAY DIFFRACTION	1.62
8Q00	X-RAY DIFFRACTION	1.62
6HEI	X-RAY DIFFRACTION	1.64
5X3N	X-RAY DIFFRACTION	1.65

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P0CG47-F1	93.74	0.88

Antibody-complex structures (SAbDab): 2 — 7NBB, 8A67

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 (11):

Position	Phenotype
48	no effect on hltf-mediated polyubiquitination of pcna.
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.
68	loss of dtx3l-mediated polyubiquitination of histone h3 and h4.
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.
76	loss of adp-ribosylation.

Function

Pathways and Gene Ontology

Reactome pathways

205 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: 742 (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, GOBP_FOREBRAIN_NEURON_DEVELOPMENT, 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, GOBP_PROTEIN_HOMOTETRAMERIZATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_NOD1_2_SIGNALING_PATHWAY

GO Biological Process (20): male meiosis I (GO:0007141), female meiosis I (GO:0007144), female gonad development (GO:0008585), protein ubiquitination (GO:0016567), modification-dependent protein catabolic process (GO:0019941), hypothalamus gonadotrophin-releasing hormone neuron development (GO:0021888), positive regulation of protein ubiquitination (GO:0031398), regulation of neuron apoptotic process (GO:0043523), mitochondrion transport along microtubule (GO:0047497), neuron projection morphogenesis (GO:0048812), protein homotetramerization (GO:0051289), regulation of mitochondrial membrane potential (GO:0051881), fat pad development (GO:0060613), regulation of proteasomal protein catabolic process (GO:0061136), seminiferous tubule development (GO:0072520), energy homeostasis (GO:0097009), positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator (GO:1902255), positive regulation of protein monoubiquitination (GO:1902527), male gonad development (GO:0008584), adipose tissue development (GO:0060612)

GO Molecular Function (4): pyridoxal phosphate binding (GO:0030170), protein tag activity (GO:0031386), ubiquitin protein ligase binding (GO:0031625), protein binding (GO:0005515)

GO Cellular Component (16): obsolete extracellular space (GO:0005615), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), 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), neuron projection (GO:0043005), neuronal cell body (GO:0043025), extracellular exosome (GO:0070062), 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
meiosis I	2
meiotic cell cycle	2
gonad development	2
intracellular membrane-bounded organelle	2
cytoplasm	2
cytoplasmic vesicle membrane	2
bounding membrane of organelle	2
male meiotic nuclear division	1
male gamete generation	1
female meiotic nuclear division	1
female gamete generation	1
development of primary female sexual characteristics	1
protein modification by small protein conjugation	1
protein catabolic process	1
protein modification process	1
modification-dependent macromolecule catabolic process	1
forebrain neuron development	1
hypothalamus gonadotrophin-releasing hormone neuron differentiation	1
protein ubiquitination	1
regulation of protein ubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
regulation of apoptotic process	1
neuron apoptotic process	1
establishment of mitochondrion localization, microtubule-mediated	1
organelle transport along microtubule	1
neuron projection development	1
plasma membrane bounded cell projection morphogenesis	1
protein homooligomerization	1
protein tetramerization	1
regulation of membrane potential	1
adipose tissue development	1
proteasomal protein catabolic process	1
regulation of protein catabolic process	1
male gonad development	1
tube development	1
reproductive structure development	1
multicellular organismal-level homeostasis	1
intrinsic apoptotic signaling pathway by p53 class mediator	1
positive regulation of signal transduction by p53 class mediator	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

566 interactions, top by confidence:

A	B	Type	Score
MAGOH	CASC3	psi-mi:“MI:0914”(association)	0.970
FANCG	FANCA	psi-mi:“MI:0914”(association)	0.960
PRPS1	PRPSAP2	psi-mi:“MI:0914”(association)	0.840
RNF20	RNF40	psi-mi:“MI:0220”(ubiquitination reaction)	0.820
UBAC1	UBB	psi-mi:“MI:0914”(association)	0.740
UBB	DAZAP2	psi-mi:“MI:0915”(physical association)	0.740
UBB	UBAC1	psi-mi:“MI:0915”(physical association)	0.740
PFDN4	PFDN6	psi-mi:“MI:0914”(association)	0.730
RAD23B	UBB	psi-mi:“MI:0914”(association)	0.670
TP53BP1	H2AC11	psi-mi:“MI:0915”(physical association)	0.670
UBB	RAD23B	psi-mi:“MI:0915”(physical association)	0.670
H2AC11	UBB	psi-mi:“MI:0915”(physical association)	0.650
FAF2	UBB	psi-mi:“MI:0914”(association)	0.640
CALCOCO2	TBKBP1	psi-mi:“MI:0914”(association)	0.640
FBXO6	MAN2B1	psi-mi:“MI:0914”(association)	0.640
COMMD8	VPS26C	psi-mi:“MI:0914”(association)	0.640
EIF2B2	SLC27A2	psi-mi:“MI:0914”(association)	0.640
YAF2	E2F6	psi-mi:“MI:0914”(association)	0.640
NICN1	TTLL1	psi-mi:“MI:0914”(association)	0.640
PSMD5	PSMD12	psi-mi:“MI:0914”(association)	0.640
UBB	SMURF2	psi-mi:“MI:0414”(enzymatic reaction)	0.620
SMURF2	UBB	psi-mi:“MI:0414”(enzymatic reaction)	0.620

BioGRID (686): UBB (Affinity Capture-MS), UBE3A (Two-hybrid), DAZAP2 (Two-hybrid), CALCOCO2 (Two-hybrid), UBQLN1 (Two-hybrid), UBB (Affinity Capture-MS), UBB (Affinity Capture-MS), DDI1 (Co-crystal Structure), DDI1 (Reconstituted Complex), UBB (Affinity Capture-MS), UBB (Affinity Capture-MS), UBB (Affinity Capture-MS), UBB (Affinity Capture-MS), UBB (Affinity Capture-MS), UBB (Affinity Capture-MS)

ESM2 similar proteins: C4YP88, P0CG47, P0CG49, P0CG51, P0CG53, P0CG54, P0CG55, P0CG60, P0CG62, P0CG63, P0CG65, P0CG67, P0CG68, P0CG70, P0CG72, P0CG73, P0CG74, P0CG75, P0CG76, P0CG77, P0CG78, P0CG79, P0CG80, P0CG81, P0CG82, P0CG83, P0CG84, P0CG85, P0CG88, P0CH04, P0CH05, P0CH27, P0CH32, P0CH33, P22589, P23324, P23398, P42739, P42740, P59669

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

2 interactions.

A	Effect	B	Mechanism
OTULIN	“up-regulates quantity”	UBB	cleavage
USP5	“up-regulates quantity”	UBB	cleavage

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 229 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
Regulation of TNFR1 signaling	9	12.9×	2e-05
TNFR1-induced NF-kappa-B signaling pathway	6	12.9×	8e-04
Regulation of TP53 Degradation	6	11.3×	1e-03
Transcriptional Regulation by E2F6	6	11.3×	1e-03
NOD1/2 Signaling Pathway	5	10.2×	6e-03
PCP/CE pathway	5	9.6×	7e-03
Ovarian tumor domain proteases	5	8.9×	9e-03
Regulation of PTEN stability and activity	6	7.1×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein K48-linked deubiquitination	5	15.7×	3e-03
protein autoubiquitination	8	9.1×	9e-04
protein K63-linked ubiquitination	7	9.1×	3e-03
protein deubiquitination	8	6.9×	4e-03
ubiquitin-dependent protein catabolic process	19	6.8×	7e-08
negative regulation of canonical NF-kappaB signal transduction	8	6.7×	4e-03
proteasome-mediated ubiquitin-dependent protein catabolic process	19	4.8×	1e-05
protein ubiquitination	20	4.0×	7e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	5
Likely benign	8
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

371 predictions. Top by Δscore:

Variant	Effect	Δscore
17:16381036:GGTGA:G	donor_gain	1.0000
17:16381895:A:AG	acceptor_gain	1.0000
17:16381900:A:AG	acceptor_gain	1.0000
17:16381900:A:AT	acceptor_loss	1.0000
17:16381901:G:GG	acceptor_gain	1.0000
17:16381901:GGTC:G	acceptor_gain	1.0000
17:16381040:A:G	donor_gain	0.9900
17:16381896:A:G	acceptor_gain	0.9900
17:16381900:AG:A	acceptor_gain	0.9900
17:16381901:GG:G	acceptor_gain	0.9900
17:16381901:GGT:G	acceptor_gain	0.9900
17:16381901:GGTCA:G	acceptor_gain	0.9900
17:16380902:G:T	donor_gain	0.9800
17:16381897:A:AG	acceptor_gain	0.9800
17:16381897:ACTAG:A	acceptor_gain	0.9800
17:16381022:GCGTC:G	donor_gain	0.9700
17:16381898:CTAGG:C	acceptor_gain	0.9700
17:16381899:TAGGT:T	acceptor_gain	0.9700
17:16381900:A:T	acceptor_gain	0.9700
17:16381901:G:T	acceptor_gain	0.9700
17:16380901:GGAAA:G	donor_gain	0.9600
17:16381898:C:G	acceptor_gain	0.9600
17:16381037:GTGA:G	donor_gain	0.9300
17:16381038:TGAT:T	donor_gain	0.9300
17:16381180:AACAG:A	donor_loss	0.9300
17:16381181:ACAG:A	donor_loss	0.9300
17:16381182:CAGG:C	donor_loss	0.9300
17:16381183:AGGTA:A	donor_loss	0.9300
17:16381184:GGTA:G	donor_loss	0.9300
17:16381185:G:C	donor_loss	0.9300

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000482226 (17:16379972 G>A,T), RS1001245226 (17:16381194 C>A,G,T), RS1002044118 (17:16379305 G>A,C,T), RS1002214625 (17:16380351 T>C,G), RS1002982998 (17:16378986 G>C,T), RS1002985978 (17:16383057 AAG>A), RS1003219014 (17:16379913 G>C), RS1003247619 (17:16383208 A>G), RS1003455638 (17:16380218 G>A), RS1004493410 (17:16382754 T>G), RS1005007568 (17:16379830 G>T), RS1005458994 (17:16381344 C>G,T), RS1006738290 (17:16381211 TG>T,TGG), RS1006957 (17:16378924 G>T), RS1006958 (17:16379140 C>T)

Disease associations

OMIM: gene MIM:191339 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
isolated cleft palate	No Known Disease Relationship	Autosomal dominant

Mondo (1): isolated cleft palate (MONDO:0007336)

Orphanet (0):

HPO phenotypes

23 total (23 of 23 shown, HPO-id order):

HPO	Term
HP:0000163	Abnormal oral cavity morphology
HP:0000185	Cleft soft palate
HP:0000193	Bifid uvula
HP:0000220	Velopharyngeal insufficiency
HP:0000327	Hypoplasia of the maxilla
HP:0000365	Hearing impairment
HP:0000403	Recurrent otitis media
HP:0000405	Conductive hearing impairment
HP:0001611	Hypernasal speech
HP:0002033	Poor suck
HP:0002463	Language impairment
HP:0002870	Obstructive sleep apnea
HP:0008376	Nasal dysarthria
HP:0008872	Feeding difficulties in infancy
HP:0009088	Speech articulation difficulties
HP:0010863	Receptive language delay
HP:0011219	Short face
HP:0011469	Nasal regurgitation
HP:0011819	Submucous cleft soft palate
HP:0011951	Aspiration pneumonia
HP:0200136	Oral-pharyngeal dysphagia
HP:0410030	Cleft lip
HP:5201016	Submucous cleft palate

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST007001_11	Cerebrospinal AB1-42 levels in normal cognition	6.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004670	beta-amyloid 1-42 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523178 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
cadmium sulfate	increases expression	3
Estradiol	decreases expression, decreases reaction, increases expression, increases reaction	3
sodium arsenite	decreases expression, increases expression	2
cobaltous chloride	increases expression	2
Acetaminophen	decreases expression, increases expression	2
Air Pollutants	increases expression, decreases expression, increases abundance	2
Cannabidiol	increases expression	2
Cisplatin	increases expression, decreases expression	2
Tobacco Smoke Pollution	increases expression	2
Cadmium Chloride	increases expression	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
moringin	decreases expression	1
bisphenol A	increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
3,3’-diindolylmethane	increases expression, increases reaction	1
ochratoxin A	decreases expression	1
dinophysistoxin 1	increases expression	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	affects cotreatment, decreases expression, decreases reaction	1
chloropicrin	increases expression	1
corosolic acid	increases expression	1
azaspiracid	increases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	increases expression	1
pyrimidifen	increases expression	1
ICG 001	increases expression	1
thifluzamide	increases expression	1
abrine	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
CHEMBL4341428	Binding	Binding affinity to UBB 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

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8RH	Abcam HCT 116 UBB KO	Cancer cell line	Male
CVCL_B9TW	Abcam A-549 UBB KO	Cancer cell line	Male
CVCL_D2HL	Abcam MCF-7 UBB KO	Cancer cell line	Female

Clinical trials (associated diseases)

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