DTX4

Summary

DTX4 (deltex E3 ubiquitin ligase 4, HGNC:29151) is a protein-coding gene on chromosome 11q12.1, encoding E3 ubiquitin-protein ligase DTX4 (Q9Y2E6). Regulator of Notch signaling, a signaling pathway involved in cell-cell communications that regulates a broad spectrum of cell-fate determinations.

Enables ubiquitin protein ligase activity. Involved in negative regulation of innate immune response; proteasome-mediated ubiquitin-dependent protein catabolic process; and protein K48-linked ubiquitination. Is active in centrosome.

Source: NCBI Gene 23220 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 100 total
• MANE Select transcript: NM_015177

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29151
Approved symbol	DTX4
Name	deltex E3 ubiquitin ligase 4
Location	11q12.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0937, RNF155
Ensembl gene	ENSG00000110042
Ensembl biotype	protein_coding
OMIM	616110
Entrez	23220

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000227451, ENST00000527475, ENST00000531902, ENST00000532982

RefSeq mRNA: 2 — MANE Select: NM_015177 NM_001300727, NM_015177

CCDS: CCDS44612, CCDS76408

Canonical transcript exons

ENST00000227451 — 9 exons

Exon	Start	End
ENSE00000990750	59192098	59192250
ENSE00000990751	59195208	59195369
ENSE00001171348	59204676	59208588
ENSE00001171358	59172132	59172806
ENSE00003512631	59189162	59189323
ENSE00003575277	59188735	59188796
ENSE00003611134	59181739	59182462
ENSE00003627197	59199684	59199773
ENSE00003655577	59191114	59191175

Expression profiles

Bgee: expression breadth ubiquitous, 268 present calls, max score 97.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.0981 / max 232.2320, expressed in 1332 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114385	8.2992	1190
114386	1.8610	706
114384	1.8366	731
114388	0.1013	47

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
inferior olivary complex	UBERON:0002127	97.56	gold quality
nasal cavity epithelium	UBERON:0005384	96.86	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	96.71	gold quality
olfactory bulb	UBERON:0002264	96.53	gold quality
ileal mucosa	UBERON:0000331	96.36	gold quality
medulla oblongata	UBERON:0001896	95.99	gold quality
inferior vagus X ganglion	UBERON:0005363	95.87	gold quality
subthalamic nucleus	UBERON:0001906	95.30	gold quality
spinal cord	UBERON:0002240	94.79	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	94.59	gold quality
superior vestibular nucleus	UBERON:0007227	94.26	gold quality
cortical plate	UBERON:0005343	94.21	gold quality
colonic mucosa	UBERON:0000317	94.09	gold quality
mucosa of sigmoid colon	UBERON:0004993	94.09	gold quality
ventral tegmental area	UBERON:0002691	93.96	gold quality
substantia nigra pars reticulata	UBERON:0001966	93.42	gold quality
ventricular zone	UBERON:0003053	93.16	gold quality
dorsal plus ventral thalamus	UBERON:0001897	92.92	gold quality
pons	UBERON:0000988	92.50	gold quality
trigeminal ganglion	UBERON:0001675	92.33	gold quality
bronchus	UBERON:0002185	92.25	gold quality
epithelium of bronchus	UBERON:0002031	92.24	gold quality
trachea	UBERON:0003126	92.23	gold quality
dorsal root ganglion	UBERON:0000044	92.19	gold quality
mucosa of urinary bladder	UBERON:0001259	92.12	gold quality
substantia nigra pars compacta	UBERON:0001965	91.90	gold quality
placenta	UBERON:0001987	91.50	gold quality
mammalian vulva	UBERON:0000997	91.30	gold quality
pylorus	UBERON:0001166	91.18	gold quality
bronchial epithelial cell	CL:0002328	90.99	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.08

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

189 targeting DTX4, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-150-5P	99.99	66.69	1976
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787

Literature-anchored findings (GeneRIF, showing 3)

• Our results provide molecular insight into the mechanisms by which NLRP4-DTX4 targets TBK1 for degradation. (PMID:22388039)
• Notch is ligand activated and undergoes DTX4-mediated ubiquitylation and bilateral endocytosis before ADAM10 processing (PMID:28611181)
• Deltex E3 ubiquitin ligase 4 promotes thyroid cancer progression through stearoyl-CoA desaturase 1. (PMID:37612343)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	dtx4a	ENSDARG00000076302
danio_rerio	dtx4b	ENSDARG00000078016
mus_musculus	Dtx4	ENSMUSG00000039982
rattus_norvegicus	Dtx4	ENSRNOG00000021086

Paralogs (4): DTX2 (ENSG00000091073), DTX1 (ENSG00000135144), DTX3L (ENSG00000163840), DTX3 (ENSG00000178498)

Protein

Protein identifiers

E3 ubiquitin-protein ligase DTX4 — Q9Y2E6 (reviewed: Q9Y2E6)

Alternative names: Protein deltex-4, RING finger protein 155, RING-type E3 ubiquitin transferase DTX4

All UniProt accessions (1): Q9Y2E6

UniProt curated annotations — full annotation on UniProt →

Function. Regulator of Notch signaling, a signaling pathway involved in cell-cell communications that regulates a broad spectrum of cell-fate determinations. Functions as a ubiquitin ligase protein in vivo, mediating ‘Lys48’-linked polyubiquitination and promoting degradation of TBK1, targeting to TBK1 requires interaction with NLRP4.

Subunit / interactions. Interacts with NLRP4.

Subcellular location. Cytoplasm.

Domain organisation. The WWE domains are thought to mediate some protein-protein interaction, and are frequently found in ubiquitin ligases.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the Deltex family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y2E6-1	1	yes
Q9Y2E6-2	2

RefSeq proteins (2): NP_001287656, NP_055992* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR004170	WWE_dom	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR018123	WWE-dom_subgr	Domain
IPR018957	Znf_C3HC4_RING-type	Domain
IPR037197	WWE_dom_sf	Homologous_superfamily
IPR039396	Deltex_C	Domain
IPR039398	Deltex_fam	Family
IPR039399	Deltex_C_sf	Homologous_superfamily

Pfam: PF00097, PF02825, PF18102

UniProt features (9 total): domain 2, region of interest 2, compositionally biased region 2, chain 1, zinc finger region 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y2E6-F1	76.83	0.48

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1606341	IRF3 mediated activation of type 1 IFN
R-HSA-2122948	Activated NOTCH1 Transmits Signal to the Nucleus
R-HSA-3134975	Regulation of innate immune responses to cytosolic DNA
R-HSA-3270619	IRF3-mediated induction of type I IFN

MSigDB gene sets: 301 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, REACTOME_SIGNALING_BY_NOTCH, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_INNATE_IMMUNE_RESPONSE, MODULE_16, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_CYTOKINE_PRODUCTION, GOCC_CENTROSOME, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_NEGATIVE_REGULATION_OF_DEFENSE_RESPONSE, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION

GO Biological Process (9): Notch signaling pathway (GO:0007219), proteasomal protein catabolic process (GO:0010498), protein ubiquitination (GO:0016567), regulation of type I interferon production (GO:0032479), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), negative regulation of innate immune response (GO:0045824), protein K48-linked ubiquitination (GO:0070936), innate immune response (GO:0045087), antiviral innate immune response (GO:0140374)

GO Molecular Function (5): ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), ubiquitin protein ligase activity (GO:0061630), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (4): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
ZBP1(DAI) mediated induction of type I IFNs	1
Signaling by NOTCH1	1
Cytosolic sensors of pathogen-associated DNA	1
STING mediated induction of host immune responses	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
innate immune response	2
cell surface receptor signaling pathway	1
protein catabolic process	1
protein modification by small protein conjugation	1
regulation of cytokine production	1
type I interferon production	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
negative regulation of response to biotic stimulus	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of innate immune response	1
negative regulation of immune response	1
protein polyubiquitination	1
immune response	1
defense response to symbiont	1
defense response to virus	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
catalytic activity	1
cation binding	1
nuclear lumen	1
intracellular anatomical structure	1
centriole	1
microtubule organizing center	1
cytoplasm	1

Protein interactions and networks

STRING

433 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DTX4	NLRP4	Q96MN2	983
DTX4	USP38	Q8NB14	692
DTX4	TBK1	Q9UHD2	621
DTX4	RNF41	Q9H4P4	437
DTX4	RNF128	Q8TEB7	418
DTX4	TRAIP	Q9BWF2	384
DTX4	TRIM27	P14373	374
DTX4	NLRP11	P59045	357
DTX4	TAX1BP1	Q86VP1	349
DTX4	PPM1B	O75688	348
DTX4	TANK	Q92844	348
DTX4	E5RHQ9	E5RHQ9	311
DTX4	TRAF3	Q13114	311
DTX4	IRF3	Q14653	305
DTX4	DYRK2	Q92630	299

IntAct

4 interactions, top by confidence:

A	B	Type	Score
DTX4	EPRS1	psi-mi:“MI:0915”(physical association)	0.400
HSP90AB1	DTX4	psi-mi:“MI:0915”(physical association)	0.400
DTX4	HPCAL1	psi-mi:“MI:0914”(association)	0.350
FTL		psi-mi:“MI:0914”(association)	0.350

BioGRID (29): NOTCH1 (Affinity Capture-Western), DTX4 (Affinity Capture-Western), DTX4 (Co-localization), DTX4 (Affinity Capture-RNA), DTX4 (Proximity Label-MS), DSTN (Affinity Capture-MS), LSM12 (Affinity Capture-MS), PSMB3 (Affinity Capture-MS), UNC45A (Affinity Capture-MS), GLOD4 (Affinity Capture-MS), HLTF (Affinity Capture-MS), DTX1 (Affinity Capture-MS), DTX3L (Affinity Capture-MS), FAT3 (Affinity Capture-MS), FAT4 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8HBI7, A0A1L8HJK9, A0A1L8HTT5, A4QP16, A6NP61, B2RVL6, C0SPG1, C3VD30, K7SGN7, O54880, P56163, Q1XFL1, Q29RJ0, Q2KI52, Q32L09, Q3V0J4, Q4R2Y2, Q4R739, Q58D79, Q5RAK6, Q5TKR9, Q5VWQ0, Q6PDK8, Q768S4, Q7T3T8, Q7T3T9, Q80T69, Q86US8, Q86Y01, Q8AW93, Q8BMD7, Q8BRB7, Q8BZ21, Q8CAK3, Q8CDN1, Q8HXK7, Q8K3Y6, Q8N2G6, Q8N9V6, Q8TE76

Diamond homologs: A1D3C5, A2A5Z6, A2QQ28, A9JRZ0, B0XQ72, B4F6W9, B8N7E5, C6KTB7, E1B7Q7, F1LP64, F1RCR6, G5E870, O00308, O13834, O14326, O15033, P33202, P40985, Q0CCL1, Q14669, Q15386, Q2TAS2, Q2UBP1, Q4WTF3, Q5BDP1, Q61010, Q6PDK8, Q757T0, Q80U95, Q86UW9, Q86Y01, Q8AW93, Q8BZZ3, Q8C863, Q8CHG5, Q8R3P2, Q96J02, Q9DBH0, Q9H0M0, Q9HAU4

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	DTX4	ubiquitination
DTX4	down-regulates	TBK1	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	84
Likely benign	1
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

1210 predictions. Top by Δscore:

Variant	Effect	Δscore
11:59172805:GG:G	donor_gain	1.0000
11:59172806:GG:G	donor_gain	1.0000
11:59181729:A:AG	acceptor_gain	1.0000
11:59181733:T:TA	acceptor_gain	1.0000
11:59182461:GG:G	donor_gain	1.0000
11:59182462:GG:G	donor_gain	1.0000
11:59188730:CACA:C	acceptor_loss	1.0000
11:59188731:ACAG:A	acceptor_gain	1.0000
11:59188732:CA:C	acceptor_loss	1.0000
11:59188733:A:AG	acceptor_gain	1.0000
11:59188733:AG:A	acceptor_gain	1.0000
11:59188734:G:GG	acceptor_gain	1.0000
11:59188734:GG:G	acceptor_gain	1.0000
11:59188794:CAGG:C	donor_loss	1.0000
11:59188795:AG:A	donor_loss	1.0000
11:59188796:GG:G	donor_loss	1.0000
11:59188797:G:GC	donor_loss	1.0000
11:59192093:CCCA:C	acceptor_loss	1.0000
11:59192094:CCA:C	acceptor_loss	1.0000
11:59192095:CA:C	acceptor_loss	1.0000
11:59192096:A:AG	acceptor_gain	1.0000
11:59192096:AG:A	acceptor_gain	1.0000
11:59192097:G:GC	acceptor_gain	1.0000
11:59192097:GG:G	acceptor_gain	1.0000
11:59192097:GGA:G	acceptor_gain	1.0000
11:59192097:GGAC:G	acceptor_gain	1.0000
11:59192097:GGACT:G	acceptor_gain	1.0000
11:59192247:CAAGG:C	donor_loss	1.0000
11:59192250:GGTC:G	donor_loss	1.0000
11:59192251:G:A	donor_loss	1.0000

AlphaMissense

4016 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:59172623:T:A	W10R	1.000
11:59172623:T:C	W10R	1.000
11:59172624:G:C	W10S	1.000
11:59172625:G:C	W10C	1.000
11:59172625:G:T	W10C	1.000
11:59172629:T:A	W12R	1.000
11:59172629:T:C	W12R	1.000
11:59172631:G:C	W12C	1.000
11:59172631:G:T	W12C	1.000
11:59172650:T:A	W19R	1.000
11:59172650:T:C	W19R	1.000
11:59172659:T:G	Y22D	1.000
11:59172684:T:A	I30N	1.000
11:59172732:T:A	L46Q	1.000
11:59172768:T:A	I58N	1.000
11:59172791:T:C	F66L	1.000
11:59172792:T:C	F66S	1.000
11:59172793:C:A	F66L	1.000
11:59172793:C:G	F66L	1.000
11:59172795:G:C	R67P	1.000
11:59181739:G:A	G71E	1.000
11:59181739:G:T	G71V	1.000
11:59181754:T:A	V76D	1.000
11:59181804:T:A	W93R	1.000
11:59181804:T:C	W93R	1.000
11:59181806:G:C	W93C	1.000
11:59181806:G:T	W93C	1.000
11:59181810:T:A	W95R	1.000
11:59181810:T:C	W95R	1.000
11:59181840:T:G	Y105D	1.000

dbSNP variants (sampled 300 via entrez): RS1000184692 (11:59198910 G>A), RS1000341302 (11:59195793 G>A), RS1000419492 (11:59207272 G>A,T), RS1000426645 (11:59183125 T>C), RS1000525654 (11:59199168 C>T), RS1000595183 (11:59200985 A>C), RS1000646382 (11:59171841 G>A), RS1000774512 (11:59196145 T>C), RS1000877521 (11:59191379 G>C,T), RS1001016829 (11:59172021 G>A), RS1001085806 (11:59174361 G>C,T), RS1001160076 (11:59205894 G>A), RS1001264239 (11:59187041 G>A,C), RS1001346640 (11:59200881 G>A,T), RS1001397746 (11:59184228 A>G)

Disease associations

OMIM: gene MIM:616110 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006364_1	Hepatitis B surface antigen seroclearance in chronic hepatitis B infection	4.000000e-06
GCST009391_1241	Metabolite levels	7.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009345	Hepatitis B virus surface antigen seropositivity
EFO:0010422	triacylglycerol 54:4 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression, decreases methylation	3
sodium arsenite	affects methylation, decreases expression	2
Acetaminophen	decreases expression	2
triphenyl phosphate	affects expression	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
2-palmitoylglycerol	increases expression	1
nutlin 3	increases expression, affects cotreatment	1
abrine	decreases expression	1
enzalutamide	affects expression	1
jinfukang	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Leflunomide	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Amphotericin B	decreases expression	1
Azathioprine	decreases expression	1
Benzo(a)pyrene	increases expression	1
Calcitriol	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Succimer	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Estradiol	decreases expression, affects cotreatment	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Lead	decreases expression	1
Lipopolysaccharides	increases expression, affects response to substance	1
Methyl Methanesulfonate	increases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7NY	Ubigene A-549 DTX4 KO	Cancer cell line	Male
CVCL_D8KC	Ubigene HCT 116 DTX4 KO	Cancer cell line	Male
CVCL_E0BY	Ubigene HeLa DTX4 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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