UBQLN1

Summary

UBQLN1 (ubiquilin 1, HGNC:12508) is a protein-coding gene on chromosome 9q21.32, encoding Ubiquilin-1 (Q9UMX0). Plays an important role in the regulation of different protein degradation mechanisms and pathways including ubiquitin-proteasome system (UPS), autophagy and endoplasmic reticulum-associated protein degradation (ERAD) pathway.

This gene encodes an ubiquitin-like protein (ubiquilin) that shares a high degree of similarity with related products in yeast, rat and frog. Ubiquilins contain an N-terminal ubiquitin-like domain and a C-terminal ubiquitin-associated domain. They physically associate with both proteasomes and ubiquitin ligases, and thus are thought to functionally link the ubiquitination machinery to the proteasome to affect in vivo protein degradation. This ubiquilin has also been shown to modulate accumulation of presenilin proteins, and it is found in lesions associated with Alzheimer’s and Parkinson’s disease. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 29979 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual disability (Limited, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 57 total — 1 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_013438

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12508
Approved symbol	UBQLN1
Name	ubiquilin 1
Location	9q21.32
Locus type	gene with protein product
Status	Approved
Aliases	DSK2, PLIC-1, XDRP1, DA41
Ensembl gene	ENSG00000135018
Ensembl biotype	protein_coding
OMIM	605046
Entrez	29979

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 19 protein_coding, 2 retained_intron

ENST00000257468, ENST00000376395, ENST00000526134, ENST00000527373, ENST00000529923, ENST00000533705, ENST00000858201, ENST00000858202, ENST00000858204, ENST00000858205, ENST00000858206, ENST00000858207, ENST00000858214, ENST00000858216, ENST00000858221, ENST00000858227, ENST00000949306, ENST00000949307, ENST00000949308, ENST00000949309, ENST00000949310

RefSeq mRNA: 2 — MANE Select: NM_013438 NM_013438, NM_053067

CCDS: CCDS6663, CCDS6664

Canonical transcript exons

ENST00000376395 — 11 exons

Exon	Start	End
ENSE00000917629	83669185	83669327
ENSE00000917630	83666350	83666433
ENSE00000982970	83686004	83686155
ENSE00001014619	83659968	83661939
ENSE00001197828	83707500	83707958
ENSE00003561226	83663875	83664043
ENSE00003565400	83682951	83683066
ENSE00003585993	83677727	83677961
ENSE00003640524	83665030	83665145
ENSE00003652600	83678441	83678599
ENSE00003656216	83679775	83680037

Expression profiles

Bgee: expression breadth ubiquitous, 261 present calls, max score 99.20.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 56.3204 / max 352.9309, expressed in 1823 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
101147	43.4423	1822
101145	6.2050	1673
101146	5.4109	1524
101148	0.8012	535
101149	0.2598	101
205536	0.2012	66

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	99.20	gold quality
cardiac muscle of right atrium	UBERON:0003379	98.85	gold quality
upper arm skin	UBERON:0004263	98.81	gold quality
tibialis anterior	UBERON:0001385	98.67	gold quality
left ventricle myocardium	UBERON:0006566	98.54	gold quality
endothelial cell	CL:0000115	98.37	gold quality
pons	UBERON:0000988	98.01	gold quality
cortical plate	UBERON:0005343	97.97	gold quality
epithelial cell of pancreas	CL:0000083	97.96	gold quality
ganglionic eminence	UBERON:0004023	97.80	gold quality
embryo	UBERON:0000922	97.79	gold quality
kidney epithelium	UBERON:0004819	97.67	gold quality
stromal cell of endometrium	CL:0002255	97.64	gold quality
upper leg skin	UBERON:0004262	97.25	gold quality
secondary oocyte	CL:0000655	97.24	gold quality
deltoid	UBERON:0001476	97.24	gold quality
thymus	UBERON:0002370	97.22	gold quality
dorsal root ganglion	UBERON:0000044	97.12	gold quality
ventricular zone	UBERON:0003053	97.06	gold quality
islet of Langerhans	UBERON:0000006	97.02	gold quality
gastrocnemius	UBERON:0001388	97.00	gold quality
superior vestibular nucleus	UBERON:0007227	96.99	gold quality
Brodmann (1909) area 46	UBERON:0006483	96.88	gold quality
corpus callosum	UBERON:0002336	96.87	gold quality
prefrontal cortex	UBERON:0000451	96.79	gold quality
muscle of leg	UBERON:0001383	96.71	gold quality
seminal vesicle	UBERON:0000998	96.57	gold quality
dorsal plus ventral thalamus	UBERON:0001897	96.57	gold quality
superior frontal gyrus	UBERON:0002661	96.53	gold quality
jejunal mucosa	UBERON:0000399	96.52	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-124858	no	201.36
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

125 targeting UBQLN1, 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-3646	100.00	73.56	5283
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-3658	99.96	73.87	4379
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-8063	99.91	69.76	3146

Literature-anchored findings (GeneRIF, showing 40)

• PLIC1 may be a regulator of HCV RNA replication through interaction with NS5B. Nn Huh7 cells that express an HCV subgenomic replicon, the amounts of both NS5B and the replicon RNA were reduced by overexpression of PLIC1. (PMID:12634373)
• Ubiquilin proteins play an important role in regulating PS protein levels in cells. (PMID:15004330)
• Ubiquilin-1 plays an active role in the precise regulation of HASH-1 and of other tissue-specific bHLH proteins (PMID:15492808)
• Our findings suggest that genetic variants in UBQLN1 on chromosome 9q22 substantially increase the risk of Alzheimer’s disease, possibly by influencing alternative splicing of this gene in the brain (PMID:15745979)
• knockdown of ubiquilin-1 and -2 protein expression by RNAi (RNA interference) increased Pen-2 and nicastrin levels (PMID:15975090)
• ubiquilin-1 limits the availability of unassembled nicotinic acetylcholine receptor subunits in neurons by drawing them to the proteosome, thus regulating nicotine-induced up-regulation (PMID:16091357)
• Genetic variation in the UBQLN1 gene has a modest effect on risk, age of onset and disease duration of Alaheimer’s disease. (PMID:16302009)
• Overexpression of ubiquilin reduces cell death in HeLa cells and primary neurons stably expressing green fluorescent protein-huntingtin fusion protein. (PMID:16461334)
• Results suggest that UBQLN1 variants do not increase risk for Alzheimer disease. (PMID:16526030)
• Ubiquilin is capable of forming dimers. Dimerization requires the central region of ubiquilin, but not its UBL or the UBA domains. Monomeric ubiquilin is likely to be the active form that is involved in binding presenilin proteins. (PMID:16813565)
• Data show that ubiquilin 1 interacts both with presenilin 1 (PS1) holoprotein and heterodimer and that the interaction between PS1 and ubiquilin 1 takes place near the cell surface. (PMID:16815845)
• UBQLN1 modulates amyloid precursor protein trafficking and Abeta secretion. (PMID:16945923)
• These results indicate a role for PLIC-1 in the protein aggregation-stress pathway, and we propose a novel function for the ubiquitin-like (UBL) domain–by means of UBL-UIM interactions–in transport to aggresomes. (PMID:17082820)
• Mutation of two lysine residues in the PS2-loop region suggested that ubiquitination is not required for interaction with ubiquilin-1 and may, in fact, even negatively regulate the interaction. (PMID:17614368)
• Our results suggest that it is unlikely that the SNP rs12344615 of the UBQLN1 gene is related to the onset of AD, PD or cognitive function. (PMID:17709205)
• Expression of the human Alzheimer’s disease-associated variant of UBQLN1 leads to more severe degeneration than does comparable expression of the human wildtype UBQLN1 in Drosophila eye. (PMID:17947293)
• The three-dimensional structure of the UBA domain of ubiquilin-1 (UQ1-UBA) free in solution and in complex with ubiquitin, is described. (PMID:18241885)
• Risk estimation for AA versus GG genotypes showed that the AA genotype is a weak risk factor for Alzheimer’s disease (PMID:18340109)
• Plic-1 may play a significant role in regulating the strength of synaptic inhibition by increasing the stability of GABA(A)Rs within the secretory pathway and thereby promoting their insertion into the neuronal plasma membrane. (PMID:18467327)
• overexpression UBQLN1 transcript variants TV1-3, but not TV4, exert a protective effect during the unfolded protein response by attenuating CHOP induction and potentially increasing cell viability. (PMID:18953672)
• UBQLN is a polyubiquitin-TDP-43 cochaperone that mediates the autophagosomal delivery and/or proteasome targeting of TDP-43 aggregates. (PMID:19112176)
• siRNA-mediated UBQLN1 depletion made cells more susceptible to starvation-induced cell death. UBQLN1 regulates cell survival during starvation. (PMID:19148225)
• Knockdown of erasin, a platform for p97/VCP and ubiquilin binding, or knockdown of ubiquilin in human cells slowed degradation of two classical endoplasmic reticulum-associated protein degradation substrates. (PMID:19822669)
• The UBQ-8i polymorphism of the UBQLN1 gene is extremely rare in Taiwan Chinese and unlikely to play a significant role in the risk of AD in Taiwan Chinese. (PMID:20350585)
• Data show that ubiquilin is degraded during both macroautophagy and during chaperone-mediated autophagy (CMA). (PMID:20529957)
• specific ubiquilin-1 transcript variants can cause PS1 accumulation and aggresome formation (PMID:21143716)
• PLIC-1 is a novel inhibitor of the TLR3-Trif antiviral pathway by reducing the abundance of Trif (PMID:21695056)
• ubiquilin-1 chaperone activity is necessary to regulate the production of APP and its fragments and that diminished ubiquilin-1 levels may contribute to AD pathogenesis. (PMID:21852239)
• Ubiquilin-1 was over-expressed following antiproliferative agents treatment of ovarian cancer cells. (PMID:22134777)
• Ubqln stabilizes BCLb protein, while also promoting monoubiquitination on multiple lysine residues and relocation to the cytosol. (PMID:22233804)
• This study demonistrated that Allele C of polymorphism UBQ-8i of the UBQLN1 gene is not an independent risk factor for mild cognitive impairment or Alzheimer’s disease (PMID:22272618)
• Genetic variants in UBQLN1 are not commonly associated with amyotrophic lateral sclerosis (PMID:22766032)
• Ubiquilin-1 immunoreactivity is concentrated on Hirano bodies and dystrophic neurites in Alzheimer’s disease (PMID:23421764)
• Targeting of Ubqln1 to autophagosomes requires the Ubqln4 UBL domain and the Ubqln1 UBA domain. (PMID:23459205)
• data suggest that ubiquilin-1 modulates gamma-secretase-mediated epsilon-site cleavage and thus may play a role in regulating gamma-secretase cleavage of various substrates. (PMID:23663107)
• results were confirmed by similar findings for ubiquilin-1 and -2 in human brain tissue sections, where accumulation was observed in huntingtin inclusions (PMID:23774650)
• The results demonstrate that in Alzheimer’s disease hippocampus, ubiquilin-1 immunoreactivity increases in the neuronal nucleoplasm and is associated with region-specific neurofibrillary changes. (PMID:23869942)
• Human ubiquilin-1 overexpression in transgenic mice increases the lifespan and delays accumulation of Huntingtin aggregates in the R6/2 mouse model of Huntington’s disease. (PMID:24475300)
• found that ZEB1 is required for induction of mesenchymal-like properties following loss of UBQLN1 and ZEB1 is capable of repressing expression of UBQLN1 (PMID:24747970)
• The results suggest that UBQ-8i polymorphism may contribute to Alzheimer’s disease susceptibility, but does not synergize with APOEepsilon4 status to increase Alzheimer’s disease risk. (PMID:25010605)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ubqln1	ENSMUSG00000005312
rattus_norvegicus	Ubqln1	ENSRNOG00000019282
drosophila_melanogaster	Ubqn	FBGN0031057
caenorhabditis_elegans	ubql-1	WBGENE00008852

Paralogs (5): UBL7 (ENSG00000138629), UBQLN4 (ENSG00000160803), UBQLNL (ENSG00000175518), UBQLN3 (ENSG00000175520), UBQLN2 (ENSG00000188021)

Protein

Protein identifiers

Ubiquilin-1 — Q9UMX0 (reviewed: Q9UMX0)

Alternative names: Protein linking IAP with cytoskeleton 1

All UniProt accessions (3): Q9UMX0, H0YDS0, H0YEZ9

UniProt curated annotations — full annotation on UniProt →

Function. Plays an important role in the regulation of different protein degradation mechanisms and pathways including ubiquitin-proteasome system (UPS), autophagy and endoplasmic reticulum-associated protein degradation (ERAD) pathway. Mediates the proteasomal targeting of misfolded or accumulated proteins for degradation by binding (via UBA domain) to their polyubiquitin chains and by interacting (via ubiquitin-like domain) with the subunits of the proteasome. Plays a role in the ERAD pathway via its interaction with ER-localized proteins UBXN4, VCP and HERPUD1 and may form a link between the polyubiquitinated ERAD substrates and the proteasome. Involved in the regulation of macroautophagy and autophagosome formation; required for maturation of autophagy-related protein LC3 from the cytosolic form LC3-I to the membrane-bound form LC3-II and may assist in the maturation of autophagosomes to autolysosomes by mediating autophagosome-lysosome fusion. Negatively regulates the TICAM1/TRIF-dependent toll-like receptor signaling pathway by decreasing the abundance of TICAM1 via the autophagic pathway. Promotes the ubiquitination and lysosomal degradation of ORAI1, consequently down-regulating the ORAI1-mediated Ca2+ mobilization. Suppresses the maturation and proteasomal degradation of amyloid beta A4 protein (A4) by stimulating the lysine 63 (K63)-linked polyubiquitination. Delays the maturation of A4 by sequestering it in the Golgi apparatus and preventing its transport to the cell surface for subsequent processing. Ubiquitinates BCL2L10 and thereby stabilizes protein abundance. Plays a role in unfolded protein response (UPR) by attenuating the induction of UPR-inducible genes, DDTI3/CHOP, HSPA5 and PDIA2 during ER stress. Plays a key role in the regulation of the levels of PSEN1 by targeting its accumulation to aggresomes which may then be removed from cells by autophagocytosis. Plays a role in unfolded protein response (UPR) by attenuating the induction of UPR-inducible genes, DDTI3/CHOP, HSPA5 and PDIA2 during ER stress. Plays a role in unfolded protein response (UPR) by attenuating the induction of UPR-inducible genes, DDTI3/CHOP, HSPA5 and PDIA2 during ER stress. Plays a key role in the regulation of the levels of PSEN1 by targeting its accumulation to aggresomes which may then be removed from cells by autophagocytosis.

Subunit / interactions. Monomer and homodimer. Heterodimer with UBQLN2. Binds CD47, NBL1, GABRA1, GABRA2, GABRA3, GABRA6, GABRB1, GABRB2 and GABRB3. Binds UBE3A, BTRC, P4HB and MTOR. Interacts with the proteasome 19S subunit. Interacts (via ubiquitin-like domain) with TREX1; the interaction is direct and may control TREX1 subcellular location. Forms a complex with UBXN4 and VCP. Interacts (via UBA domain) with UBQLN4 (via ubiquitin-like domain). Found in a complex with UBQLN2 and MAP1LC3A/B/C. The monomeric form interacts with PSEN2. The monomeric form interacts with PSEN1. Interacts with ORAI1. Interacts (via UBA domain) with TICAM1. Interacts with EPS15. Interacts (via UBA domain) with UBA52 and (via ubiquitin-like domain) with PSMD3 and PSMD4. Interacts with HERPUD1. Interacts with MAP1LC3A/B/C in the presence of UBQLN4. Interacts (via ubiquitin-like domain) with EPS15 (via UIM domains) and both the ubiquitinated and non-ubiquitinated forms can interact with EPS15. Interacts (via ubiquitin-like domain) with EPS15L1, HGS (via UIM domain) and STAM2 (via UIM domain). Interacts with BCL2L10/BCL-B; in the cytoplasm. Monomeric form interacts with PSEN1. Monomeric form interacts with PSEN1.

Subcellular location. Cytoplasm. Nucleus. Endoplasmic reticulum. Cytoplasmic vesicle. Autophagosome. Cell membrane.

Tissue specificity. Brain (at protein level). Ubiquitous. Highly expressed throughout the brain; detected in neurons and in neuropathological lesions, such as neurofibrillary tangles and Lewy bodies. Highly expressed in heart, placenta, pancreas, lung, liver, skeletal muscle and kidney.

Post-translational modifications. Degraded during both macroautophagy and during chaperone-mediated autophagy (CMA). Phosphorylated. Ubiquitinated.

Domain organisation. The UBA domain mediates binding to PSEN1 and PSEN2. It also binds ubiquitin with micromolar affinity, independently of polyubiquitin linkage type. Essential for its association with microtubule-associated protein 1 light chain 3 (MAP1LC3). The ubiquitin-like domain mediates its association with the subunits of the proteasome. Dimerization is dependent upon the central region of the protein containing the STI1 domains and is independent of its ubiquitin-like and UBA domains.

Miscellaneous. May be a prognostic marker for lung adenocarcinoma patient clinical outcome.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9UMX0-1	1	yes
Q9UMX0-2	2
Q9UMX0-3	3
Q9UMX0-4	4

RefSeq proteins (2): NP_038466, NP_444295 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000626	Ubiquitin-like_dom	Domain
IPR006636	STI1_HS-bd	Domain
IPR009060	UBA-like_sf	Homologous_superfamily
IPR015496	Ubiquilin	Family
IPR015940	UBA	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily

Pfam: PF00240, PF00627, PF23195

UniProt features (45 total): compositionally biased region 8, sequence conflict 7, domain 6, helix 6, region of interest 5, strand 5, splice variant 4, initiator methionine 1, chain 1, modified residue 1, turn 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
2JY5	SOLUTION NMR
2JY6	SOLUTION NMR
2KLC	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UMX0-F1	64.30	0.05

Functional residue map

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

Post-translational modifications (1): 2

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis

MSigDB gene sets: 305 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_NEGATIVE_REGULATION_OF_TRANSPORTER_ACTIVITY, GOBP_VACUOLE_ORGANIZATION, NKX25_02, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, REACTOME_MEMBRANE_TRAFFICKING, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_MACROAUTOPHAGY, ATGTTAA_MIR302C, LINDGREN_BLADDER_CANCER_CLUSTER_2A_DN, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION

GO Biological Process (17): autophagosome assembly (GO:0000045), ubiquitin-dependent protein catabolic process (GO:0006511), macroautophagy (GO:0016236), regulation of macroautophagy (GO:0016241), regulation of protein ubiquitination (GO:0031396), positive regulation of protein ubiquitination (GO:0031398), negative regulation of toll-like receptor 3 signaling pathway (GO:0034140), response to endoplasmic reticulum stress (GO:0034976), aggrephagy (GO:0035973), ERAD pathway (GO:0036503), cellular response to hypoxia (GO:0071456), autophagosome maturation (GO:0097352), negative regulation of store-operated calcium channel activity (GO:1901340), regulation of oxidative stress-induced intrinsic apoptotic signaling pathway (GO:1902175), positive regulation of ERAD pathway (GO:1904294), autophagy (GO:0006914), negative regulation of transport (GO:0051051)

GO Molecular Function (4): kinase binding (GO:0019900), polyubiquitin modification-dependent protein binding (GO:0031593), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (13): proteasome complex (GO:0000502), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), autophagosome (GO:0005776), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), plasma membrane (GO:0005886), aggresome (GO:0016235), cytoplasmic vesicle (GO:0031410), protein-containing complex (GO:0032991), perinuclear region of cytoplasm (GO:0048471), nucleus (GO:0005634), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Clathrin-mediated endocytosis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cytoplasm	4
protein ubiquitination	3
macroautophagy	3
cellular response to stress	2
intracellular membrane-bounded organelle	2
Atg12 activating enzyme activity	1
protein-phosphatidylethanolamide deconjugating activity	1
Atg12 conjugating enzyme activity	1
Atg12 ligase activity	1
organelle assembly	1
Atg1/ULK1 kinase complex assembly	1
autophagosome organization	1
modification-dependent protein catabolic process	1
autophagosome assembly	1
autophagy	1
regulation of autophagy	1
regulation of protein modification by small protein conjugation or removal	1
regulation of protein ubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
toll-like receptor 3 signaling pathway	1
regulation of toll-like receptor 3 signaling pathway	1
negative regulation of cytoplasmic pattern recognition receptor signaling pathway	1
proteasomal protein catabolic process	1
response to endoplasmic reticulum stress	1
response to chemical	1
response to hypoxia	1
cellular response to decreased oxygen levels	1
protein-containing complex disassembly	1
store-operated calcium channel activity	1
negative regulation of calcium ion transmembrane transporter activity	1
regulation of store-operated calcium channel activity	1
intrinsic apoptotic signaling pathway in response to oxidative stress	1
regulation of intrinsic apoptotic signaling pathway	1
ERAD pathway	1
positive regulation of proteasomal protein catabolic process	1
regulation of ERAD pathway	1
positive regulation of response to endoplasmic reticulum stress	1
catabolic process	1
transmembrane transport	1

Protein interactions and networks

STRING

4892 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UBQLN1	CD47	Q08722	944
UBQLN1	PSMD4	P55036	934
UBQLN1	ATXN3	P54252	921
UBQLN1	ATXN3L	Q9H3M9	921
UBQLN1	UBE4B	O95155	869
UBQLN1	UBE4A	Q14139	869
UBQLN1	PSEN1	P49768	862
UBQLN1	VCP	P55072	843
UBQLN1	UBL7	Q96S82	828
UBQLN1	ADRM1	Q16186	826
UBQLN1	HSPA13	P48723	812
UBQLN1	DDI1	Q8WTU0	783
UBQLN1	UBE3A	P78355	748
UBQLN1	STIP1	P31948	746
UBQLN1	APP	P05067	745

IntAct

1184 interactions, top by confidence:

A	B	Type	Score
UBQLN1	SERPINI2	psi-mi:“MI:0915”(physical association)	0.900
SERPINI2	UBQLN1	psi-mi:“MI:0915”(physical association)	0.900
HSPA13	UBQLN1	psi-mi:“MI:0915”(physical association)	0.830
UBQLN1	UBE2V1	psi-mi:“MI:0915”(physical association)	0.810
UBE2V1	UBQLN1	psi-mi:“MI:0915”(physical association)	0.810
ZG16	UBQLN1	psi-mi:“MI:0915”(physical association)	0.780
UBQLN1	CSTF2	psi-mi:“MI:0915”(physical association)	0.780
UBQLN1	PLAAT3	psi-mi:“MI:0915”(physical association)	0.780
NGLY1	UBQLN1	psi-mi:“MI:0915”(physical association)	0.780
UBQLN1	CSTF2T	psi-mi:“MI:0915”(physical association)	0.780
TRIM32	UBQLN1	psi-mi:“MI:0915”(physical association)	0.780
CSTF2	UBQLN1	psi-mi:“MI:0915”(physical association)	0.780
PLAAT3	UBQLN1	psi-mi:“MI:0915”(physical association)	0.780
UBQLN1	NGLY1	psi-mi:“MI:0915”(physical association)	0.780
CSTF2T	UBQLN1	psi-mi:“MI:0915”(physical association)	0.780
UBQLN1	ZG16	psi-mi:“MI:0915”(physical association)	0.780
TMEM31	UBQLN1	psi-mi:“MI:0915”(physical association)	0.740
UBQLN1	TMEM31	psi-mi:“MI:0915”(physical association)	0.740
RTL8C	UBQLN1	psi-mi:“MI:0915”(physical association)	0.720
UBQLN1	AGR2	psi-mi:“MI:0915”(physical association)	0.720
GYPB	UBQLN1	psi-mi:“MI:0915”(physical association)	0.720
COL1A2	UBQLN1	psi-mi:“MI:0915”(physical association)	0.720
SRGN	UBQLN1	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (675): UBQLN1 (Two-hybrid), UBQLN1 (Two-hybrid), UBQLN1 (Two-hybrid), UBQLN1 (Two-hybrid), UBQLN1 (Two-hybrid), UBQLN1 (Two-hybrid), UBQLN1 (Two-hybrid), UBQLN1 (Two-hybrid), UBQLN1 (Two-hybrid), UBQLN1 (Two-hybrid), UBQLN1 (Two-hybrid), UBQLN1 (Two-hybrid), UBQLN1 (Two-hybrid), UBQLN1 (Two-hybrid), UBQLN1 (Two-hybrid)

ESM2 similar proteins: A1L5A6, A2VDN6, A4IGK4, O00401, O08816, O12940, O35226, O43395, O48726, O60784, O88746, P40855, P50503, P55036, Q15459, Q16186, Q2KIA6, Q3SZD1, Q4WTC0, Q58DA0, Q5R5F1, Q5R684, Q5R7U2, Q5XHH7, Q5ZLF0, Q60415, Q62698, Q68FJ8, Q6GN67, Q6NRL6, Q6NZ09, Q6P877, Q6PDL0, Q7ZXD6, Q84L30, Q84L31, Q84L33, Q8BUR9, Q8K4Z5, Q8R1Q8

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

1 interactions.

A	Effect	B	Mechanism
SMURF1	unknown	UBQLN1	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 70 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
Activation of STAT3 by cadherin engagement	5	22.1×	2e-04
FCERI mediated NF-kB activation	5	21.1×	2e-04
CLEC7A (Dectin-1) signaling	5	19.3×	2e-04
Downstream TCR signaling	5	17.3×	2e-04
Interleukin-1 signaling	5	16.8×	2e-04
Separation of Sister Chromatids	5	8.2×	2e-03
Antigen processing: Ubiquitination & Proteasome degradation	6	6.0×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	33
Likely benign	8
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
402173	NM_013438.5(UBQLN1):c.377del (p.Asn126fs)	Likely pathogenic

SpliceAI

1974 predictions. Top by Δscore:

Variant	Effect	Δscore
9:83661940:C:CC	acceptor_gain	1.0000
9:83663872:TA:T	donor_loss	1.0000
9:83663873:ACC:A	donor_loss	1.0000
9:83663874:C:G	donor_loss	1.0000
9:83664043:CCTAC:C	acceptor_loss	1.0000
9:83664044:C:CC	acceptor_gain	1.0000
9:83664044:C:T	acceptor_loss	1.0000
9:83665028:AC:A	donor_gain	1.0000
9:83665029:CC:C	donor_gain	1.0000
9:83666348:A:AC	donor_gain	1.0000
9:83666349:C:CC	donor_gain	1.0000
9:83669181:TCA:T	donor_loss	1.0000
9:83669182:CA:C	donor_loss	1.0000
9:83669183:ACCT:A	donor_loss	1.0000
9:83669184:C:A	donor_loss	1.0000
9:83669336:T:C	acceptor_gain	1.0000
9:83669336:T:TC	acceptor_gain	1.0000
9:83669342:T:C	acceptor_gain	1.0000
9:83669342:T:TC	acceptor_gain	1.0000
9:83677728:T:TA	donor_gain	1.0000
9:83677957:CCAAA:C	acceptor_gain	1.0000
9:83677958:CAAAC:C	acceptor_gain	1.0000
9:83678409:C:CA	donor_gain	1.0000
9:83678616:C:CT	acceptor_gain	1.0000
9:83678616:C:T	acceptor_gain	1.0000
9:83678617:A:T	acceptor_gain	1.0000
9:83679766:T:A	donor_gain	1.0000
9:83679773:A:AC	donor_gain	1.0000
9:83679774:C:CC	donor_gain	1.0000
9:83679774:CTTGT:C	donor_gain	1.0000

AlphaMissense

3907 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:83661809:A:G	L583S	1.000
9:83661818:A:T	I580N	1.000
9:83661821:G:T	A579D	1.000
9:83661822:C:G	A579P	1.000
9:83661836:C:A	G574V	1.000
9:83661836:C:T	G574D	1.000
9:83661846:C:G	A571P	1.000
9:83661851:A:G	L569P	1.000
9:83661851:A:T	L569Q	1.000
9:83661854:G:T	A568D	1.000
9:83661855:C:G	A568P	1.000
9:83661880:A:C	F559L	1.000
9:83661880:A:T	F559L	1.000
9:83661881:A:C	F559C	1.000
9:83661881:A:G	F559S	1.000
9:83661882:A:C	F559V	1.000
9:83661882:A:G	F559L	1.000
9:83661882:A:T	F559I	1.000
9:83661884:C:A	G558V	1.000
9:83661884:C:T	G558E	1.000
9:83661885:C:G	G558R	1.000
9:83661885:C:T	G558R	1.000
9:83661896:A:G	L554P	1.000
9:83661896:A:T	L554H	1.000
9:83661905:A:G	L551P	1.000
9:83665060:A:G	L473S	1.000
9:83665073:C:G	G469R	1.000
9:83665081:A:C	I466S	1.000
9:83665081:A:G	I466T	1.000
9:83665081:A:T	I466N	1.000

dbSNP variants (sampled 300 via entrez): RS1000001557 (9:83707140 G>C), RS1000081685 (9:83676752 T>A,C), RS1000102072 (9:83697353 C>G), RS1000109798 (9:83690915 A>C), RS1000158764 (9:83703942 T>A), RS1000242262 (9:83673500 A>C,G), RS1000313581 (9:83708835 A>C), RS1000331218 (9:83668276 T>C), RS1000388871 (9:83697714 C>T), RS1000401539 (9:83673206 G>A,T), RS1000432939 (9:83661786 G>C), RS1000441823 (9:83704281 T>C), RS1000570104 (9:83662508 T>C), RS1000624151 (9:83662345 T>C), RS1000733276 (9:83707147 C>A,T)

Disease associations

OMIM: gene MIM:605046 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability	Limited	Autosomal dominant

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

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST009391_981	Metabolite levels	9.000000e-06
GCST010002_322	Refractive error	6.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010538	taurocholate measurement

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): CHEMBL6067208 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.22	Kd	0.598	nM	CHEMBL5653589
9.20	ED50	0.627	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 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	2149716: Binding affinity to human UBQLN1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0006	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	increases expression, affects cotreatment	4
bisphenol A	affects expression, decreases expression, increases expression	3
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Cyclosporine	increases expression	2
Copper Sulfate	increases expression	2
Particulate Matter	increases abundance, increases expression, decreases response to substance	2
triphenyl phosphate	affects expression	1
methylparaben	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
ochratoxin A	decreases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	increases stability	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	increases reaction, affects binding	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
jinfukang	decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Zoledronic Acid	increases expression	1
Arsenic Trioxide	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Arbutin	increases expression	1
Arsenic	increases expression, affects cotreatment, increases abundance	1
Vehicle Emissions	decreases response to substance, increases expression	1
Dinitrochlorobenzene	affects binding	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
CHEMBL5652758	Binding	Binding affinity to human UBQLN1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

7 cell lines: 6 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2KB	Abcam HeLa UBQLN1 KO	Cancer cell line	Female
CVCL_D9VB	Ubigene HEK293 UBQLN1 KO	Transformed cell line	Female
CVCL_DX65	HAP1 UBQLN1 (-) UBQLN4 (-) 1	Cancer cell line	Male
CVCL_DX66	HAP1 UBQLN1 (-) UBQLN4 (-) 2	Cancer cell line	Male
CVCL_E1DW	Ubigene U2OS UBQLN1 KO	Cancer cell line	Female
CVCL_TW07	HAP1 UBQLN1 (-) 2	Cancer cell line	Male
CVCL_TW08	HAP1 UBQLN1 (-) 3	Cancer cell line	Male

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