TNIP3

Summary

TNIP3 (TNFAIP3 interacting protein 3, HGNC:19315) is a protein-coding gene on chromosome 4q27, encoding TNFAIP3-interacting protein 3 (Q96KP6). Binds to zinc finger protein TNFAIP3 and inhibits NF-kappa-B activation induced by tumor necrosis factor, Toll-like receptor 4 (TLR4), interleukin-1 and 12-O-tetradecanoylphorbol-13-acetate.

Enables polyubiquitin modification-dependent protein binding activity. Involved in cellular response to lipopolysaccharide; negative regulation of canonical NF-kappaB signal transduction; and pattern recognition receptor signaling pathway. Predicted to be located in cytosol.

Source: NCBI Gene 79931 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 19 total
• MANE Select transcript: NM_024873

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19315
Approved symbol	TNIP3
Name	TNFAIP3 interacting protein 3
Location	4q27
Locus type	gene with protein product
Status	Approved
Aliases	LIND, FLJ21162, ABIN-3
Ensembl gene	ENSG00000050730
Ensembl biotype	protein_coding
OMIM	608019
Entrez	79931

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 6 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000057513, ENST00000506753, ENST00000507879, ENST00000509841, ENST00000511909, ENST00000515036, ENST00000515605, ENST00000868872, ENST00000868873

RefSeq mRNA: 3 — MANE Select: NM_024873 NM_001128843, NM_001244764, NM_024873

CCDS: CCDS3718, CCDS58925, CCDS58926

Canonical transcript exons

ENST00000057513 — 11 exons

Exon	Start	End
ENSE00001599724	121131408	121132662
ENSE00002075592	121164060	121164321
ENSE00003493113	121142726	121142776
ENSE00003527850	121147049	121147174
ENSE00003538566	121138624	121138684
ENSE00003543440	121161136	121161216
ENSE00003555616	121157094	121157243
ENSE00003591641	121154551	121154679
ENSE00003621715	121141816	121141914
ENSE00003638822	121150103	121150219
ENSE00003640568	121158687	121158752

Expression profiles

Bgee: expression breadth ubiquitous, 138 present calls, max score 80.32.

FANTOM5 (CAGE): breadth broad, TPM avg 6.9659 / max 660.2492, expressed in 401 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
53793	6.7585	325
53797	0.0834	52
53796	0.0690	38
53792	0.0549	25

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.32	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	73.78	silver quality
colonic epithelium	UBERON:0000397	72.20	gold quality
vermiform appendix	UBERON:0001154	71.56	gold quality
caecum	UBERON:0001153	66.53	gold quality
lymph node	UBERON:0000029	64.47	gold quality
gall bladder	UBERON:0002110	63.01	gold quality
stromal cell of endometrium	CL:0002255	62.38	gold quality
upper lobe of left lung	UBERON:0008952	58.12	gold quality
upper lobe of lung	UBERON:0008948	57.99	gold quality
jejunal mucosa	UBERON:0000399	56.84	silver quality
lower lobe of lung	UBERON:0008949	55.93	silver quality
prefrontal cortex	UBERON:0000451	55.50	gold quality
tonsil	UBERON:0002372	55.49	gold quality
lung	UBERON:0002048	55.39	gold quality
rectum	UBERON:0001052	55.19	gold quality
smooth muscle tissue	UBERON:0001135	54.04	gold quality
granulocyte	CL:0000094	53.92	gold quality
spleen	UBERON:0002106	53.21	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	52.37	gold quality
blood	UBERON:0000178	52.35	gold quality
cerebellar vermis	UBERON:0004720	52.00	gold quality
omental fat pad	UBERON:0010414	51.13	gold quality
peritoneum	UBERON:0002358	51.10	gold quality
bone marrow cell	CL:0002092	50.99	gold quality
adipose tissue of abdominal region	UBERON:0007808	50.55	gold quality
leukocyte	CL:0000738	50.54	gold quality
right lung	UBERON:0002167	50.19	gold quality
islet of Langerhans	UBERON:0000006	49.68	gold quality
monocyte	CL:0000576	49.64	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.21
E-GEOD-124858	no	326.32
E-HCAD-30	no	41.64

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): IRF6, NFKB1, NFKB, RELA

miRNA regulators (miRDB)

49 targeting TNIP3, 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-8485	100.00	77.57	4731
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-202-3P	99.84	71.41	1290
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-2113	99.58	71.22	1521
HSA-MIR-4269	99.55	69.89	1373
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-4728-3P	99.47	68.94	981
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-505-3P	99.19	69.71	896
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-6830-5P	99.01	68.73	1884

Literature-anchored findings (GeneRIF, showing 9)

• ABIN-3 is a novel negative feedback regulator of LPS-induced NF-kappaB activation (PMID:17088249)
• ABIN-3 is, thus, an IL-10-induced gene product capable of attenuating NF-kappaB in human macrophages yet is inoperative in mice and represents a basis for species-specific differences in IL-10 actions. (PMID:17485448)
• Enhanced expression of ABIN-3 in monocytes is associated with sepsis (PMID:18081698)
• This review defines ABIN-3 based on three different parameters: ability to bind A20; ability to inhibit NF-kappaB activation upon overexpression; the presence of specific short amino acid regions of strong homology, designated ABIN homology domains. (PMID:19464428)
• adiponectin augmented the expression of A20, suppressor of cytokine signaling (SOCS) 3, B-cell CLL/lymphoma (BCL) 3, TNF receptor-associated factor (TRAF) 1, and TNFAIP3-interacting protein (TNIP) 3. (PMID:19617629)
• recombinant transgene facilitates the transcription of pro-inflammatory cytokines in fibroblast-like synoviocytes in rheumatoid arthritis (PMID:22093807)
• TNIP3 expression is significantly upregulated in human masticatory mucosa during wound healing (PMID:28005267)
• Elevated TNIP3 mRNA Expression in TNF-alpha-Secreting Cells from Patients with Major Depressive Disorder. (PMID:31307045)
• TNFAIP3 Interacting Protein 3 Overexpression Suppresses Nonalcoholic Steatohepatitis by Blocking TAK1 Activation. (PMID:32268115)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tnip3	ENSMUSG00000044162
rattus_norvegicus	Tnip3	ENSRNOG00000064111

Paralogs (2): TNIP1 (ENSG00000145901), TNIP2 (ENSG00000168884)

Protein

Protein identifiers

TNFAIP3-interacting protein 3 — Q96KP6 (reviewed: Q96KP6)

Alternative names: A20-binding inhibitor of NF-kappa-B activation 3, Listeria-induced gene protein

All UniProt accessions (2): Q96KP6, H0Y9J7

UniProt curated annotations — full annotation on UniProt →

Function. Binds to zinc finger protein TNFAIP3 and inhibits NF-kappa-B activation induced by tumor necrosis factor, Toll-like receptor 4 (TLR4), interleukin-1 and 12-O-tetradecanoylphorbol-13-acetate. Overexpression inhibits NF-kappa-B-dependent gene expression in response to lipopolysaccharide at a level downstream of TRAF6 and upstream of IKBKB. NF-kappa-B inhibition is independent of TNFAIP3 binding.

Subunit / interactions. Interacts with TNFAIP3. Interacts with polyubiquitin.

Tissue specificity. Highly expressed in lung, lymph node, thymus and fetal liver. Expressed at lower levels in bone marrow, brain, kidney, spleen, leukocytes and tonsils. Could be detected in heart, salivary gland, adrenal gland, pancreas, ovary and fetal brain. High levels detected in liver, colon, small intestine, muscle, stomach, testis, placenta, thyroid, uterus, prostate, skin and PBL.

Induction. By Listeria infection. Expression is slightly down-regulated by dexamethasone and slightly up-regulated by IL-10. Strongly induced mRNA and protein expression by lipopolysaccharide.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96KP6-1	1	yes
Q96KP6-2	2
Q96KP6-3	3

RefSeq proteins (3): NP_001122315, NP_001231693, NP_079149* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR032419	CC2-LZ_dom	Domain

Pfam: PF16516

UniProt features (13 total): region of interest 3, splice variant 3, sequence conflict 2, chain 1, mutagenesis site 1, coiled-coil region 1, compositionally biased region 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96KP6-F1	80.10	0.59

Functional residue map

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

Mutagenesis-validated functional residues (1):

Position	Phenotype
214–215	abolishes ubiquitin binding; loss of inhibitory activity on nf-kappa-b activation.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5689896	Ovarian tumor domain proteases

MSigDB gene sets: 154 (showing top): GOBP_INFLAMMATORY_RESPONSE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_TOLL_LIKE_RECEPTOR_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, NFKB_C, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, RUTELLA_RESPONSE_TO_CSF2RB_AND_IL4_UP, TGIF_01, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND

GO Biological Process (7): MyD88-independent toll-like receptor signaling pathway (GO:0002756), regulation of transcription by RNA polymerase II (GO:0006357), inflammatory response (GO:0006954), toll-like receptor 4 signaling pathway (GO:0034142), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), cellular response to lipopolysaccharide (GO:0071222), regulation of canonical NF-kappaB signal transduction (GO:0043122)

GO Molecular Function (2): polyubiquitin modification-dependent protein binding (GO:0031593), protein binding (GO:0005515)

GO Cellular Component (2): cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Deubiquitination	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
canonical NF-kappaB signal transduction	2
cellular anatomical structure	2
toll-like receptor signaling pathway	1
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
defense response	1
cell surface toll-like receptor signaling pathway	1
regulation of canonical NF-kappaB signal transduction	1
negative regulation of intracellular signal transduction	1
response to lipopolysaccharide	1
cellular response to molecule of bacterial origin	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
regulation of intracellular signal transduction	1
modification-dependent protein binding	1
binding	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

754 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNIP3	TNIP2	Q8NFZ5	763
TNIP3	TNFAIP3	P21580	653
TNIP3	IRAK3	Q9Y616	390
TNIP3	TOP2A	P11388	383
TNIP3	EAPP	Q56P03	367
TNIP3	GPBP1	Q86WP2	346
TNIP3	LY6D	Q14210	342
TNIP3	KRT36	O76013	337
TNIP3	DRG2	P55039	332
TNIP3	TNFAIP2	Q03169	330
TNIP3	CLEC4D	Q8WXI8	326
TNIP3	ZCCHC4	Q9H5U6	323
TNIP3	ARFGEF3	Q5TH69	316
TNIP3	ETV3	P41162	313
TNIP3	KCNK7	Q9Y2U2	307

IntAct

129 interactions, top by confidence:

A	B	Type	Score
TAX1BP1	TNIP3	psi-mi:“MI:0915”(physical association)	0.780
TNIP3	TAX1BP1	psi-mi:“MI:0915”(physical association)	0.780
TNIP1	TNIP3	psi-mi:“MI:0915”(physical association)	0.720
TNIP3	DAZAP2	psi-mi:“MI:0915”(physical association)	0.720
LZTS2	TNIP3	psi-mi:“MI:0915”(physical association)	0.720
TNIP3	TNIP1	psi-mi:“MI:0915”(physical association)	0.720
DAZAP2	TNIP3	psi-mi:“MI:0915”(physical association)	0.720
TNIP3	LZTS2	psi-mi:“MI:0915”(physical association)	0.720
KRT40	TNIP3	psi-mi:“MI:0915”(physical association)	0.600
TNIP3	KRT40	psi-mi:“MI:0915”(physical association)	0.600
TNIP3	TNFAIP3	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-8	TNIP3	psi-mi:“MI:0915”(physical association)	0.560
TNIP3	NOTCH2NLA	psi-mi:“MI:0915”(physical association)	0.560
TNIP3	ZBTB8A	psi-mi:“MI:0915”(physical association)	0.560
TNIP3		psi-mi:“MI:0915”(physical association)	0.560
NOTCH2NLA	TNIP3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (53): TNIP3 (Two-hybrid), TNIP3 (Two-hybrid), TNIP3 (Two-hybrid), TNIP3 (Two-hybrid), TNIP3 (Two-hybrid), LZTS2 (Two-hybrid), KRT40 (Two-hybrid), KRTAP10-8 (Two-hybrid), KRTAP10-3 (Two-hybrid), NOTCH2NL (Two-hybrid), ZBTB8A (Two-hybrid), TNIP3 (Affinity Capture-MS), TNIP3 (Synthetic Lethality), PIBF1 (Two-hybrid), KPNA3 (Two-hybrid)

ESM2 similar proteins: A0JMQ7, A2BGP7, A4D2H0, A4FU28, B4F7A7, O75665, P0C219, P0CG41, Q05D60, Q15025, Q28BZ7, Q28C41, Q2T9X8, Q32LC2, Q499E4, Q4PJT6, Q4R7I4, Q5FWP9, Q5U3Z6, Q5U465, Q5XIA0, Q5XJA2, Q5ZJA3, Q6AXZ4, Q6NRH3, Q6P926, Q6PCG6, Q7M6Y5, Q80Z25, Q865V0, Q86UF2, Q86W54, Q86XR8, Q86YF9, Q86Z20, Q8BMD2, Q8CEE0, Q8IX94, Q8IYJ2, Q8IYX8

Diamond homologs: Q15025, Q96KP6, Q9WUU8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	12
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1953 predictions. Top by Δscore:

Variant	Effect	Δscore
4:121141809:TAC:T	donor_loss	1.0000
4:121141810:A:AC	donor_gain	1.0000
4:121141810:ACT:A	donor_loss	1.0000
4:121141811:C:CC	donor_gain	1.0000
4:121141811:CTTA:C	donor_gain	1.0000
4:121141812:T:TC	donor_loss	1.0000
4:121141813:TA:T	donor_loss	1.0000
4:121141814:A:AC	donor_gain	1.0000
4:121141814:ACTGG:A	donor_loss	1.0000
4:121141815:C:CC	donor_gain	1.0000
4:121141815:C:G	donor_loss	1.0000
4:121141815:CT:C	donor_gain	1.0000
4:121141815:CTG:C	donor_gain	1.0000
4:121141815:CTGG:C	donor_gain	1.0000
4:121141912:CAT:C	acceptor_gain	1.0000
4:121142721:CATA:C	donor_loss	1.0000
4:121142722:ATACC:A	donor_loss	1.0000
4:121142723:TAC:T	donor_loss	1.0000
4:121142724:ACCTG:A	donor_loss	1.0000
4:121142725:C:CT	donor_loss	1.0000
4:121142772:TTTAT:T	acceptor_gain	1.0000
4:121142773:TTAT:T	acceptor_gain	1.0000
4:121142774:TAT:T	acceptor_gain	1.0000
4:121142775:ATCT:A	acceptor_gain	1.0000
4:121142776:TCTAA:T	acceptor_loss	1.0000
4:121142777:C:CC	acceptor_gain	1.0000
4:121146864:A:C	donor_gain	1.0000
4:121150090:T:TA	donor_gain	1.0000
4:121150097:TCTCA:T	donor_loss	1.0000
4:121150098:CTCA:C	donor_loss	1.0000

AlphaMissense

2171 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:121158729:C:A	W57C	0.995
4:121158729:C:G	W57C	0.995
4:121147131:C:G	R218P	0.994
4:121158731:A:G	W57R	0.993
4:121158731:A:T	W57R	0.993
4:121147140:C:G	R215P	0.991
4:121147151:G:C	F211L	0.990
4:121147151:G:T	F211L	0.990
4:121147153:A:G	F211L	0.990
4:121158717:A:C	F61L	0.989
4:121158717:A:T	F61L	0.989
4:121158719:A:G	F61L	0.989
4:121158751:A:G	L50P	0.988
4:121147154:G:C	D210E	0.986
4:121147154:G:T	D210E	0.986
4:121158730:C:G	W57S	0.983
4:121147156:C:G	D210H	0.981
4:121154558:A:G	L162P	0.981
4:121147152:A:G	F211S	0.979
4:121147155:T:G	D210A	0.979
4:121147101:A:G	L228P	0.978
4:121147122:A:G	L221P	0.978
4:121154561:C:G	R161P	0.978
4:121147155:T:A	D210V	0.970
4:121150113:A:G	L200P	0.970
4:121147142:T:A	E214D	0.969
4:121147142:T:G	E214D	0.969
4:121147155:T:C	D210G	0.969
4:121157233:A:G	L75P	0.962
4:121158718:A:G	F61S	0.961

dbSNP variants (sampled 300 via entrez): RS1000015819 (4:121133031 A>T), RS1000031884 (4:121168596 T>A,C), RS10000692 (4:121157162 T>C,G), RS1000069922 (4:121193822 C>T), RS1000086631 (4:121200967 G>A,T), RS1000120074 (4:121215594 C>A), RS1000202845 (4:121157502 A>G), RS1000308465 (4:121198161 TA>T), RS1000308526 (4:121162395 A>C), RS1000354117 (4:121203952 A>T), RS10004021 (4:121158376 T>C,G), RS10004221 (4:121202423 G>T), RS10004623 (4:121219946 A>G), RS1000473075 (4:121222925 C>A,G), RS1000481140 (4:121209150 C>T)

Disease associations

OMIM: gene MIM:608019 | 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
GCST001879_2	Breast cancer	3.000000e-07
GCST009597_145	Multiple sclerosis	1.000000e-10

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs116665727	TNIP3		0.00	0

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	2
Asian ginseng	decreases reaction, increases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
ethyl-p-hydroxybenzoate	increases expression	1
cupric chloride	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
abrine	increases expression	1
gardiquimod	decreases reaction, increases expression	1
Temozolomide	decreases expression	1
Zoledronic Acid	increases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	increases expression	1
Diethylhexyl Phthalate	decreases reaction, increases expression	1
Lipopolysaccharides	increases expression, affects response to substance, affects cotreatment	1
Malathion	increases expression	1
Silicon Dioxide	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Cadmium Chloride	decreases expression	1
Protein Kinase Inhibitors	decreases reaction, increases expression	1

Clinical trials (associated diseases)

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