TNIP1

Summary

TNIP1 (TNFAIP3 interacting protein 1, HGNC:16903) is a protein-coding gene on chromosome 5q33.1, encoding TNFAIP3-interacting protein 1 (Q15025). Inhibits NF-kappa-B activation and TNF-induced NF-kappa-B-dependent gene expression by regulating TAX1BP1 and A20/TNFAIP3-mediated deubiquitination of IKBKG; proposed to link A20/TNFAIP3 to ubiquitinated IKBKG.

This gene encodes an A20-binding protein which plays a role in autoimmunity and tissue homeostasis through the regulation of nuclear factor kappa-B activation. Mutations in this gene have been associated with psoriatic arthritis, rheumatoid arthritis, and systemic lupus erythematosus. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 10318 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 62
• Clinical variants (ClinVar): 445 total — 2 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 44
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_006058

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16903
Approved symbol	TNIP1
Name	TNFAIP3 interacting protein 1
Location	5q33.1
Locus type	gene with protein product
Status	Approved
Aliases	NAF1, KIAA0113, ABIN-1, VAN
Ensembl gene	ENSG00000145901
Ensembl biotype	protein_coding
OMIM	607714
Entrez	10318

Gene structure

Transcript identifiers

Ensembl transcripts: 49 — 42 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000315050, ENST00000389378, ENST00000517329, ENST00000518977, ENST00000519339, ENST00000520695, ENST00000520931, ENST00000521001, ENST00000521423, ENST00000521591, ENST00000521782, ENST00000522100, ENST00000522226, ENST00000522574, ENST00000522926, ENST00000523200, ENST00000523338, ENST00000524280, ENST00000610535, ENST00000714530, ENST00000878007, ENST00000878008, ENST00000878009, ENST00000878010, ENST00000878011, ENST00000878012, ENST00000878013, ENST00000878014, ENST00000878015, ENST00000878016, ENST00000878017, ENST00000878018, ENST00000878019, ENST00000878020, ENST00000878021, ENST00000878022, ENST00000878023, ENST00000878024, ENST00000878025, ENST00000878026, ENST00000878027, ENST00000878028, ENST00000878029, ENST00000878030, ENST00000949031, ENST00000949032, ENST00000949033, ENST00000949034, ENST00000949035

RefSeq mRNA: 12 — MANE Select: NM_006058 NM_001252385, NM_001252386, NM_001252390, NM_001252391, NM_001252392, NM_001252393, NM_001258454, NM_001258455, NM_001258456, NM_001364486, NM_001364487, NM_006058

CCDS: CCDS34280, CCDS58982, CCDS58983, CCDS58984, CCDS58985, CCDS75359

Canonical transcript exons

ENST00000521591 — 18 exons

Exon	Start	End
ENSE00000972914	151062127	151062212
ENSE00000972915	151060318	151060395
ENSE00000972916	151056766	151056957
ENSE00000972917	151052165	151052259
ENSE00000972918	151049824	151049947
ENSE00000972919	151045861	151045950
ENSE00000972920	151042896	151042961
ENSE00000972922	151039097	151039225
ENSE00000972923	151036790	151036921
ENSE00001273460	151064960	151065131
ENSE00001505688	151042540	151042671
ENSE00002124998	151080880	151081034
ENSE00003463862	151033608	151033799
ENSE00003519404	151035002	151035067
ENSE00003597877	151035582	151035707
ENSE00003604760	151032287	151032383
ENSE00003672337	151063613	151063747
ENSE00004282574	151029945	151030747

Expression profiles

Bgee: expression breadth ubiquitous, 298 present calls, max score 98.15.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 79.0806 / max 1645.3123, expressed in 1826 samples.

FANTOM5 promoters (16 alternative TSS)

Promoter ID	TPM avg	Samples expressed
64311	45.0164	1826
64321	26.3838	974
64310	3.4507	971
64312	1.1834	737
64309	1.0649	374
64320	0.9712	329
64324	0.3343	106
64302	0.1614	33
64322	0.1172	60
64303	0.0871	21

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	98.15	gold quality
blood	UBERON:0000178	98.05	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.93	gold quality
colonic epithelium	UBERON:0000397	97.74	gold quality
apex of heart	UBERON:0002098	97.69	gold quality
gastrocnemius	UBERON:0001388	97.64	gold quality
gluteal muscle	UBERON:0002000	97.40	gold quality
bone marrow cell	CL:0002092	97.35	gold quality
muscle of leg	UBERON:0001383	97.35	gold quality
granulocyte	CL:0000094	97.26	gold quality
cartilage tissue	UBERON:0002418	97.25	gold quality
spleen	UBERON:0002106	97.09	gold quality
amniotic fluid	UBERON:0000173	96.96	gold quality
small intestine Peyer’s patch	UBERON:0003454	96.92	gold quality
subcutaneous adipose tissue	UBERON:0002190	96.91	gold quality
adipose tissue	UBERON:0001013	96.86	gold quality
tonsil	UBERON:0002372	96.80	gold quality
connective tissue	UBERON:0002384	96.70	gold quality
small intestine	UBERON:0002108	96.66	gold quality
adipose tissue of abdominal region	UBERON:0007808	96.64	gold quality
upper lobe of left lung	UBERON:0008952	96.61	gold quality
omental fat pad	UBERON:0010414	96.60	gold quality
peritoneum	UBERON:0002358	96.57	gold quality
muscle organ	UBERON:0001630	96.54	gold quality
skeletal muscle organ	UBERON:0014892	96.54	gold quality
monocyte	CL:0000576	96.51	gold quality
vermiform appendix	UBERON:0001154	96.51	gold quality
leukocyte	CL:0000738	96.45	gold quality
mucosa of transverse colon	UBERON:0004991	96.41	gold quality
mononuclear cell	CL:0000842	96.39	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.22

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, NFKB, PAX3, PPARA, PPARG, RARA, SP1, SP3

miRNA regulators (miRDB)

45 targeting TNIP1, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-2116-3P	99.74	64.32	889
HSA-MIR-9851-3P	99.63	69.68	1110
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-5004-3P	99.54	68.27	1371
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-3182	99.40	68.15	2454
HSA-MIR-593-5P	99.34	69.50	965
HSA-MIR-6815-3P	99.13	68.98	1530
HSA-MIR-1207-3P	98.99	66.22	1532
HSA-MIR-3194-3P	98.83	66.22	1167
HSA-MIR-760	98.81	66.65	1392
HSA-MIR-2276-3P	98.76	67.75	1384
HSA-MIR-4635	98.74	67.63	1339
HSA-MIR-6769B-5P	98.73	64.91	1092
HSA-MIR-7977	98.65	66.18	2590
HSA-MIR-676-5P	98.49	68.87	1492

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• A new ERK2 binding protein, Naf1, attenuates the EGF/ERK2 nuclear signaling. (PMID:12220502)
• TNF-alpha induces Naf1 gene expression in synoviocytes. (PMID:12965196)
• alternative splicing and role implicated in interaction with HIV-1 (PMID:14526201)
• NAF1 is required for accumulation of human box H/ACA, snoRNPs, scaRNPs, and telomerase. (PMID:16601202)
• ABIN-1 physically links A20 to NEMO/IKKgamma and facilitates A20-mediated de-ubiquitination of NEMO/IKKgamma, thus resulting in inhibition of NF-kappaB (PMID:16684768)
• Novel splice variants of the Naf1 gene were identified. (PMID:17016622)
• NAF1 associates with mature H/ACA RNA (PMID:17135485)
• an important role for ubiquitin binding in the negative regulation of NF-kappaB signaling by ABINs and identify UBAN as a novel UBD. (PMID:18212736)
• role for an ABIN-sensitive non-classical NF-kappaB signalling pathway in the proliferation of EGFR-overexpressing tumour cells. (PMID:18622428)
• Expanded catalog of genetic loci implicated in psoriasis susceptibility. (PMID:19169254)
• This review defines ABIN-1 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)
• the effects of ABIN-1 on p105 processing and of p105 on stabilizing ABIN-1 act to potentiate the NF-kappaB inhibitory activity of ABIN-1. (PMID:19695220)
• TNIP1 interacts with liganded RARalpha and RARgamma but acts as a corepressor of their activity. (PMID:19732752)
• identified five new systemic lupus erythematosus susceptibility loci (P < 5 x 10(-8)): TNIP1 (odds ratio (OR) = 1.27), PRDM1 (OR = 1.20), JAZF1 (OR = 1.20), UHRF1BP1 (OR = 1.17) and IL10 (OR = 1.19). (PMID:19838195)
• Significant associations were found for the single nucleotide polymorphism rs10036748 of TNIP1 with photosensitivity and vasculitis in patients with systemic lupus erythematosus (PMID:20516000)
• Association of TNIP1 with systemic lupus erythematosus was confirmed in a Japanese population (PMID:20849588)
• A20, ABIN-1/2, and CARD11 mutations have prognostic value in gastrointestinal diffuse large B-cell lymphoma (PMID:21266526)
• the interaction of ABIN1 with polyubiquitin is required to limit the activation of TLR-MyD88 pathways and prevent autoimmunity (PMID:21606507)
• The IL23A and TNIP1 genes showed convincing evidence for association SNPs mapping to previously reported psoriasis loci show evidence for association to PSA. (PMID:21623003)
• The researchers found a genotype association of SNP rs1808593 NOS3 polymorphisms and HIE. (PMID:21674837)
• A markedly reduced expression of the TNIP1 gene and also its protein product were observed both in lesional skin tissue and in cultured dermal fibroblasts from SSc(Systemic sclerosis) patients. (PMID:21750679)
• ABIN1 requires its ubiquitin binding domain and cooperates with TAX1BP1 and A20 to restrict antiviral signaling. (PMID:21885437)
• The requirements for TNIP1-peroxisome proliferator activated receptor (PPAR) interaction are characteristic for coactivators; however, TNIP1 partially decreases PPAR activity. (PMID:21967852)
• The TNIP1 distal promoter, approximately 4600 nucleotides upstream of a frequently utilized transcription start site region, contains PPAR-gamma and NF-kappaB sites that bind the respective transcription factors in vivo. (PMID:22001530)
• Data indicate that TNFAIP3, ETS1 and TNIP1 are probably common susceptibility genes for systemic lupus erythematosus (SLE) in Chinese populations, and they may contribute to the pathogenesis of multiple SLE subphenotypes. (PMID:22087647)
• recombinant transgene facilitates the transcription of pro-inflammatory cytokines in fibroblast-like synoviocytes in rheumatoid arthritis (PMID:22093807)
• The varying levels and distribution of TNIP1 in normal and disease state tissues could be expected to affect processes in which TNIP1 is involved (PMID:22147607)
• we integrate the current knowledge of TNIP1s functions with the diseases in which it has been associated to potentially elucidate the role this regulator has in promoting or alleviating these inflammatory diseases[review] (PMID:22542476)
• Our results confirm the association signals between systemic lupus erythematosus and TNIP1 variants in multiple populations and provide new insight into the mechanism by which TNIP1 variants may contribute to SLE pathogenesis. (PMID:22833143)
• These data confirmed the influence of TNIP1 on an increased susceptibility to systemic sclerosis and reinforced this locus as a common autoimmunity risk factor. (PMID:22896740)
• This study demonistrated that (151) Pro–>Ala change in TNIP1 association to myasthenia gravis. (PMID:23055271)
• Analysis of the TNIP1 promoter reveals multiple transcription start sites in its GC-rich proximal regions along with two transcriptionally active specificity protein (SP) sites, responsive to both Sp1 and Sp3. (PMID:23464785)
• TNIP1/ANXA6 and CSMD1 variants interacting with cigarette smoking and alcohol intake affect risk of psoriasis. (PMID:23541940)
• Analysis of SNP in the TNIP1 gene and expression of this gene in peripheral blood lymphocytes indicated these SNP were associated with the occurrence of systemic lupus erythematosus in Han Chinese patients. (PMID:23858047)
• Data indicate significant multiplicative interaction observed between NFKB1 rs28362491 and TNIP1 rs3792783 in systemic lupus erythematosus. (PMID:23911423)
• We conclude that polymorphisms in TNIP1 are associated with antibody-positive primary Sjogren’s syndrome. (PMID:23944604)
• variants in the TNIP1 gene are associated with the risk for lupus nephritis and could be mechanistically involved in disease development via aberrant regulation of NF-kappaB and mitogen-activated protein kinase activity. (PMID:23970121)
• Report role of TNIP1 genetic variants in confering risk of systemic lupus erythematosus in Chinese population. (PMID:24091983)
• TNIP1 polymorphism may be a risk factor for VKH syndrome in Han Chinese (PMID:24788730)
• Single-nucleotide polymorphisms rs7708392 and rs495881 in TNIP1 were significantly associated with Lupus Nephritis in individuals with European or African ancestry. (PMID:25034154)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tnip1	ENSDARG00000015653
mus_musculus	Tnip1	ENSMUSG00000020400
rattus_norvegicus	Tnip1	ENSRNOG00000010370

Paralogs (2): TNIP3 (ENSG00000050730), TNIP2 (ENSG00000168884)

Protein

Protein identifiers

TNFAIP3-interacting protein 1 — Q15025 (reviewed: Q15025)

Alternative names: A20-binding inhibitor of NF-kappa-B activation 1, HIV-1 Nef-interacting protein, Nef-associated factor 1, Nip40-1, Virion-associated nuclear shuttling protein

All UniProt accessions (7): A0A0A0MRZ4, A0AAQ5BI70, E7EMV7, Q15025, E7EW15, E7EW68, E7EWG2

UniProt curated annotations — full annotation on UniProt →

Function. Inhibits NF-kappa-B activation and TNF-induced NF-kappa-B-dependent gene expression by regulating TAX1BP1 and A20/TNFAIP3-mediated deubiquitination of IKBKG; proposed to link A20/TNFAIP3 to ubiquitinated IKBKG. Involved in regulation of EGF-induced ERK1/ERK2 signaling pathway; blocks MAPK3/MAPK1 nuclear translocation and MAPK1-dependent transcription. Increases cell surface CD4(T4) antigen expression. Involved in the anti-inflammatory response of macrophages and positively regulates TLR-induced activation of CEBPB. Involved in the prevention of autoimmunity; this function implicates binding to polyubiquitin. Involved in leukocyte integrin activation during inflammation; this function is mediated by association with SELPLG and dependent on phosphorylation by SRC-family kinases. Interacts with HIV-1 matrix protein and is packaged into virions and overexpression can inhibit viral replication. May regulate matrix nuclear localization, both nuclear import of PIC (Preintegration complex) and export of GAG polyprotein and viral genomic RNA during virion production. In case of infection, promotes association of IKBKG with Shigella flexneri E3 ubiquitin-protein ligase ipah9.8 p which in turn promotes polyubiquitination of IKBKG leading to its proteasome-dependent degradation and thus is perturbing NF-kappa-B activation during bacterial infection.

Subunit / interactions. Interacts with TNFAIP3 and IKBKG (polyubiquitinated); facilitates TNFAIP3-mediated de-ubiquitination of NEMO/IKBKG. Interacts with polyubiquitin. Interacts with MAPK1, SELPLG and PIK3CD. Interacts with IRAK1 (polyubiquitinated). Interacts with MYD88; the interaction is indicative for participation in an activated TLR-signaling complex. Interacts with HIV-1 matrix protein. Interacts with TAX1BP1. (Microbial infection) Interacts with Shigella flexneri ipah9.8; the interaction promotes polyubiquitination of IKBKG.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Ubiquitous. Strongly expressed in peripheral blood lymphocytes, spleen and skeletal muscle, and is weakly expressed in the brain. In peripheral blood mononucleocytes, isoform 4 is mainly expressed and isoform 1 and isoform 7 are almost not expressed. Expression of isoform 1 and isoform 7 increases in leukemic cells.

Post-translational modifications. Phosphorylation at Tyr-552 by SRC-family kinases recruits phosphoinositide-3-kinase (PI3K) PIK3CD:p85 heterodimer which results in integrin activation and leukocyte adhesion to activated endothelium during inflammation.

Miscellaneous. Less effective in the NF-kappa-B inhibitory effect.

Isoforms (8)

UniProt ID	Names	Canonical?
Q15025-1	1, Alpha, FL	yes
Q15025-2	2, Beta
Q15025-3	3
Q15025-4	4, Alpha2
Q15025-5	5, Alpha4
Q15025-6	6, Beta2
Q15025-7	7, Alpha3, Beta3
Q15025-8	8, Beta4

RefSeq proteins (12): NP_001239314, NP_001239315, NP_001239319, NP_001239320, NP_001239321, NP_001239322, NP_001245383, NP_001245384, NP_001245385, NP_001351415, NP_001351416, NP_006049* (*=MANE)

Domains & families (InterPro)

UniProt features (52 total): modified residue 10, splice variant 9, sequence variant 9, region of interest 7, coiled-coil region 3, compositionally biased region 3, sequence conflict 3, mutagenesis site 2, helix 2, chain 1, short sequence motif 1, turn 1, strand 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
9D34	X-RAY DIFFRACTION	1.42
8YFL	X-RAY DIFFRACTION	1.5
8YFM	X-RAY DIFFRACTION	1.5
8YFK	X-RAY DIFFRACTION	2
8YFN	X-RAY DIFFRACTION	2.3
7EAL	X-RAY DIFFRACTION	2.5
7EAO	X-RAY DIFFRACTION	2.9
7EB9	X-RAY DIFFRACTION	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15025-F1	72.47	0.42

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 (10): 77, 284, 403, 438, 442, 552, 571, 599, 599, 627

Mutagenesis-validated functional residues (2):

Position	Phenotype
472	abolishes binding to polyubiquitin (‘k-63’-linked and linear).
552	abolishes interaction with pi3k p85 regulatory subunit and abolishes interaction between selplg and pi3k p85 regulatory

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5689896	Ovarian tumor domain proteases

MSigDB gene sets: 615 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_DN, GOBP_RNA_TEMPLATED_DNA_BIOSYNTHETIC_PROCESS, GOBP_CHROMOSOME_ORGANIZATION, CREL_01, GOBP_NEGATIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, GOBP_RIBOSOME_BIOGENESIS, chr4q32, GOBP_POSITIVE_REGULATION_OF_DNA_BIOSYNTHETIC_PROCESS, GOBP_INFLAMMATORY_RESPONSE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_NEGATIVE_REGULATION_OF_VIRAL_PROCESS, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, DITTMER_PTHLH_TARGETS_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS

GO Biological Process (17): MyD88-dependent toll-like receptor signaling pathway (GO:0002755), regulation of transcription by RNA polymerase II (GO:0006357), translation (GO:0006412), defense response (GO:0006952), inflammatory response (GO:0006954), leukocyte cell-cell adhesion (GO:0007159), glycoprotein biosynthetic process (GO:0009101), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), negative regulation of viral genome replication (GO:0045071), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of inflammatory response (GO:0050729), negative regulation of ERK1 and ERK2 cascade (GO:0070373), cellular response to lipopolysaccharide (GO:0071222), positive regulation of protein deubiquitination (GO:1903003), positive regulation of macromolecule metabolic process (GO:0010604), regulation of canonical NF-kappaB signal transduction (GO:0043122), regulation of primary metabolic process (GO:0080090)

GO Molecular Function (3): identical protein binding (GO:0042802), mitogen-activated protein kinase binding (GO:0051019), protein binding (GO:0005515)

GO Cellular Component (4): nucleoplasm (GO:0005654), cytosol (GO:0005829), nucleus (GO:0005634), 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
cellular anatomical structure	3
transcription by RNA polymerase II	2
macromolecule biosynthetic process	2
canonical NF-kappaB signal transduction	2
toll-like receptor signaling pathway	1
regulation of DNA-templated transcription	1
peptidyltransferase activity	1
translational initiation	1
translational elongation	1
translational termination	1
protein metabolic process	1
protein biosynthetic process	1
response to stress	1
defense response	1
cell-cell adhesion	1
glycoprotein metabolic process	1
carbohydrate derivative biosynthetic process	1
regulation of canonical NF-kappaB signal transduction	1
negative regulation of intracellular signal transduction	1
viral genome replication	1
regulation of viral genome replication	1
negative regulation of viral process	1
regulation of transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
inflammatory response	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
regulation of inflammatory response	1
negative regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	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
protein deubiquitination	1
regulation of protein deubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
positive regulation of metabolic process	1
macromolecule metabolic process	1

Protein interactions and networks

STRING

1403 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNIP1	TNFAIP3	P21580	997
TNIP1	TNIP2	Q8NFZ5	718
TNIP1	IRF5	Q13568	713
TNIP1	NFKB1	P19838	675
TNIP1	TAX1BP1	Q86VP1	672
TNIP1	IL23R	Q5VWK5	667
TNIP1	ERAP1	Q9NZ08	660
TNIP1	LCE3C	Q5T5A8	649
TNIP1	CYLD	Q9NQC7	640
TNIP1	TRAF3IP2	O43734	621
TNIP1	TNF	P01375	615
TNIP1	TRAF6	Q9Y4K3	608
TNIP1	RNF11	Q9Y3C5	606
TNIP1	RNF114	Q9Y508	593
TNIP1	LCE3D	Q9BYE3	591

IntAct

468 interactions, top by confidence:

A	B	Type	Score
IKBKG	IKBKB	psi-mi:“MI:0914”(association)	0.980
TNIP1	OPTN	psi-mi:“MI:0915”(physical association)	0.970
OPTN	TNIP1	psi-mi:“MI:0915”(physical association)	0.970
CEP97	CCP110	psi-mi:“MI:2364”(proximity)	0.950
TNFAIP3	TNIP1	psi-mi:“MI:0915”(physical association)	0.930
TNIP1	TNFAIP3	psi-mi:“MI:0915”(physical association)	0.930
NDC80	TNIP1	psi-mi:“MI:0915”(physical association)	0.830
CCNG1	TNIP1	psi-mi:“MI:0915”(physical association)	0.830
TCEA2	TNIP1	psi-mi:“MI:0915”(physical association)	0.830
TNIP1	NME7	psi-mi:“MI:0915”(physical association)	0.830
TNIP1	CCNG1	psi-mi:“MI:0915”(physical association)	0.830
NME7	TNIP1	psi-mi:“MI:0915”(physical association)	0.830

BioGRID (1433): TNIP1 (Two-hybrid), TNIP1 (Two-hybrid), TNIP1 (Two-hybrid), TNIP1 (Two-hybrid), TNIP1 (Two-hybrid), TNIP1 (Two-hybrid), TNIP1 (Two-hybrid), TNIP1 (Two-hybrid), TNIP1 (Two-hybrid), TNIP1 (Two-hybrid), TNIP1 (Two-hybrid), TNIP1 (Two-hybrid), TNIP1 (Two-hybrid), TNIP1 (Two-hybrid), TNIP1 (Two-hybrid)

ESM2 similar proteins: A0A8I3QA39, A0JNT9, A0PJT0, A1YB07, A2A6T1, A2A9T0, A4FUG8, A7MCY6, D3YV10, E1U8D0, F1MRK3, G3V735, G9G127, O75145, O94964, P60469, P60853, P97817, Q01850, Q08379, Q15025, Q499E4, Q5RCR6, Q5SPX1, Q5U465, Q5U4W1, Q5XIA0, Q5ZJA3, Q61043, Q62835, Q62839, Q6DG50, Q6DIS8, Q6NZT2, Q86X02, Q86YS3, Q8BMK0, Q8BQP8, Q8CFC9, Q8IYE1

Diamond homologs: Q15025, Q96KP6, Q9WUU8

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
TBK1	“down-regulates quantity by destabilization”	TNIP1	phosphorylation
TNIP1	“up-regulates activity”	TAX1BP1	relocalization
TNIP1	“down-regulates activity”	TRAF3	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 90 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
TNFR1-induced proapoptotic signaling	9	68.2×	4e-13
TNFR1-induced NF-kappa-B signaling pathway	11	63.7×	2e-15
TNF signaling	8	58.3×	4e-11
Regulation of TNFR1 signaling	12	46.3×	2e-15
NOD1/2 Signaling Pathway	5	27.4×	2e-05
Loss of Nlp from mitotic centrosomes	8	21.9×	8e-08
Loss of proteins required for interphase microtubule organization from the centrosome	8	21.9×	8e-08
Recruitment of mitotic centrosome proteins and complexes	9	21.1×	2e-08

GO biological processes:

GO term	Partners	Fold	FDR
canonical NF-kappaB signal transduction	11	53.0×	3e-14
centriole replication	5	48.2×	8e-06
negative regulation of canonical NF-kappaB signal transduction	14	31.7×	6e-15
tumor necrosis factor-mediated signaling pathway	5	21.7×	2e-04
obsolete positive regulation of NF-kappaB transcription factor activity	5	13.5×	2e-03
positive regulation of canonical NF-kappaB signal transduction	12	11.5×	1e-07
cellular response to tumor necrosis factor	5	10.8×	3e-03
T cell receptor signaling pathway	5	10.0×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	3
Uncertain significance	283
Likely benign	92
Benign	9

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
2501711	NM_138386.3(NAF1):c.984dup (p.Ser329fs)	Pathogenic
2501712	NM_138386.3(NAF1):c.956_957del (p.Lys319fs)	Pathogenic
1338525	NM_138386.3(NAF1):c.1033+1G>T	Likely pathogenic
2443184	NM_138386.3(NAF1):c.1033+1G>A	Likely pathogenic
2443185	NM_138386.3(NAF1):c.691A>T (p.Lys231Ter)	Likely pathogenic

SpliceAI

4371 predictions. Top by Δscore:

Variant	Effect	Δscore
4:163129355:G:GC	acceptor_gain	1.0000
4:163129372:A:C	acceptor_gain	1.0000
4:163133153:CCAGG:C	donor_gain	1.0000
4:163133256:CCT:C	acceptor_gain	1.0000
4:163133258:T:C	acceptor_gain	1.0000
4:163133258:T:TC	acceptor_gain	1.0000
4:163140215:GTACT:G	donor_loss	1.0000
4:163140216:TACTT:T	donor_loss	1.0000
4:163140217:ACTT:A	donor_loss	1.0000
4:163140218:CTTA:C	donor_gain	1.0000
4:163140218:CTTAC:C	donor_loss	1.0000
4:163140219:TTA:T	donor_loss	1.0000
4:163140220:TA:T	donor_loss	1.0000
4:163140221:A:AC	donor_gain	1.0000
4:163140221:ACTGT:A	donor_loss	1.0000
4:163140222:C:CC	donor_gain	1.0000
4:163140222:CT:C	donor_gain	1.0000
4:163140222:CTG:C	donor_gain	1.0000
4:163140222:CTGT:C	donor_gain	1.0000
4:163140222:CTGTT:C	donor_gain	1.0000
4:163140285:AGTCT:A	donor_gain	1.0000
4:163140381:TAT:T	acceptor_gain	1.0000
4:163140381:TATCT:T	acceptor_loss	1.0000
4:163140382:ATCT:A	acceptor_loss	1.0000
4:163140383:TC:T	acceptor_loss	1.0000
4:163140384:C:CA	acceptor_loss	1.0000
4:163140384:C:CC	acceptor_gain	1.0000
4:163140385:T:A	acceptor_loss	1.0000
4:163145778:AAACC:A	donor_loss	1.0000
4:163145779:AACCT:A	donor_loss	1.0000

AlphaMissense

4154 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:151035664:C:G	R480P	1.000
5:151042938:C:A	W320C	1.000
5:151042938:C:G	W320C	1.000
5:151042940:A:G	W320R	1.000
5:151042940:A:T	W320R	1.000
5:151035658:C:G	R482P	0.999
5:151035665:G:T	R480S	0.999
5:151035673:C:G	R477P	0.999
5:151035684:G:C	F473L	0.999
5:151035684:G:T	F473L	0.999
5:151035685:A:G	F473S	0.999
5:151035686:A:G	F473L	0.999
5:151039104:A:G	L419P	0.999
5:151042939:C:G	W320S	0.999
5:151042960:A:G	L313P	0.999
5:151045868:C:G	R310P	0.999
5:151052243:A:G	L215P	0.999
5:151035634:A:G	L490P	0.998
5:151035674:G:T	R477S	0.998
5:151035685:A:C	F473C	0.998
5:151035688:T:G	D472A	0.998
5:151035689:C:G	D472H	0.998
5:151035696:G:C	F469L	0.998
5:151035696:G:T	F469L	0.998
5:151035698:A:G	F469L	0.998
5:151042574:A:G	L367P	0.998
5:151042661:A:G	L338P	0.998
5:151042926:G:C	F324L	0.998
5:151042926:G:T	F324L	0.998
5:151042928:A:G	F324L	0.998

dbSNP variants (sampled 300 via entrez): RS1000057796 (5:151041899 A>T), RS1000109663 (5:151042097 C>T), RS1000210003 (5:151086609 T>C), RS1000260714 (5:151086357 G>T), RS1000297213 (5:151068063 A>G), RS1000427502 (5:151063469 G>A,T), RS1000470237 (5:151053733 C>T), RS1000521086 (5:151064977 T>C), RS1000555891 (5:151080819 G>A), RS1000631725 (5:151059328 C>T), RS1000720993 (5:151047810 A>G), RS1000734485 (5:151070786 G>A), RS1000754219 (5:151061797 G>A), RS1000828552 (5:151084529 C>T), RS1000870757 (5:151031731 T>C)

Disease associations

OMIM: gene MIM:607714 | disease phenotypes: MIM:620365

GenCC curated gene-disease

Disease	Classification	Inheritance
pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7	Strong	Autosomal dominant
systemic lupus erythematosus	Supportive	Unknown

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7	Definitive	AD

Mondo (4): pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7 (MONDO:0957261), pulmonary fibrosis (MONDO:0002771), amyotrophic lateral sclerosis (MONDO:0004976), systemic lupus erythematosus (MONDO:0007915)

Orphanet (1): Amyotrophic lateral sclerosis (Orphanet:803)

HPO phenotypes

44 total (30 of 44 shown, HPO-id order):

HPO	Term
HP:0000093	Proteinuria
HP:0000155	Oral ulcer
HP:0000488	Retinopathy
HP:0000716	Depression
HP:0000790	Hematuria
HP:0000822	Hypertension
HP:0000992	Cutaneous photosensitivity
HP:0001250	Seizure
HP:0001369	Arthritis
HP:0001596	Alopecia
HP:0001824	Weight loss
HP:0001873	Thrombocytopenia
HP:0001878	Hemolytic anemia
HP:0001882	Decreased total leukocyte count
HP:0001945	Fever
HP:0002039	Anorexia
HP:0002072	Chorea
HP:0002716	Lymphadenopathy
HP:0003453	Antineutrophil antibody positivity
HP:0003493	Antinuclear antibody positivity
HP:0005421	Decreased circulating complement C3 concentration
HP:0005764	Polyarticular arthritis
HP:0007417	Discoid lupus rash
HP:0012085	Pyuria
HP:0012378	Fatigue
HP:0020151	Anti-dsDNA antibody positivity
HP:0025300	Malar rash
HP:0030880	Raynaud phenomenon
HP:0032235	Anti-La/SS-B antibody positivity
HP:0033028	Anti-U1 ribonucleoprotein antibody positivity

GWAS associations

62 associations (top):

Study	Trait	p-value
GCST000322_2	Psoriasis	1.000000e-20
GCST000507_2	Systemic lupus erythematosus	2.000000e-09
GCST000519_11	Hair morphology	4.000000e-06
GCST001146_7	Systemic sclerosis	5.000000e-09
GCST001611_6	Myasthenia gravis	3.000000e-10
GCST001725_71	Inflammatory bowel disease	3.000000e-37
GCST001795_30	Systemic lupus erythematosus	3.000000e-06
GCST002069_11	Systemic lupus erythematosus and Systemic sclerosis	2.000000e-08
GCST002528_1	Colorectal cancer	8.000000e-09
GCST002738_13	Psoriasis	1.000000e-18
GCST002740_12	Inflammatory skin disease	4.000000e-38
GCST002874_4	Psoriasis	3.000000e-07
GCST002874_41	Psoriasis	4.000000e-14
GCST003155_49	Systemic lupus erythematosus	1.000000e-45
GCST003156_16	Systemic lupus erythematosus	4.000000e-24
GCST003252_25	Systemic lupus erythematosus	2.000000e-11
GCST003268_20	Psoriasis vulgaris	4.000000e-37
GCST003269_6	Cutaneous psoriasis	2.000000e-14
GCST003270_6	Psoriatic arthritis	3.000000e-23
GCST003622_28	Systemic lupus erythematosus	2.000000e-18
GCST003622_46	Systemic lupus erythematosus	3.000000e-06
GCST004131_47	Inflammatory bowel disease	3.000000e-15
GCST004132_24	Crohn’s disease	2.000000e-19
GCST004600_164	Eosinophil percentage of white cells	7.000000e-14
GCST004606_133	Eosinophil count	7.000000e-16
GCST004617_109	Eosinophil percentage of granulocytes	1.000000e-11
GCST004623_13	Neutrophil percentage of granulocytes	2.000000e-11
GCST004624_80	Sum eosinophil basophil counts	2.000000e-14
GCST004744_23	Lung adenocarcinoma	2.000000e-07
GCST004748_41	Lung cancer	9.000000e-06

EFO canonical traits (16, from GWAS)

EFO ID	Trait name
EFO:0005038	hair morphology
EFO:1001494	psoriasis vulgaris
EFO:0007773	cutaneous psoriasis measurement
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004842	eosinophil count
EFO:0007996	eosinophil percentage of granulocytes
EFO:0007994	neutrophil percentage of granulocytes
EFO:0005090	basophil count
EFO:0008328	chronotype measurement
EFO:0004644	TPE interval measurement
EFO:0007768	response to exercise
EFO:0007828	daytime rest measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004587	lymphocyte count
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
D008180	Lupus Erythematosus, Systemic	C17.300.480; C20.111.590
D011658	Pulmonary Fibrosis	C08.381.483.652; C23.550.355.644

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
rs2233302	GPX3, TNIP1		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, affects cotreatment, increases abundance	4
Arsenic	decreases expression, affects cotreatment, increases abundance, increases expression	3
cobaltous chloride	increases expression	2
methacrylaldehyde	affects cotreatment, increases expression, increases oxidation, increases abundance	2
Acrolein	affects cotreatment, increases expression, increases oxidation, increases abundance	2
Benzo(a)pyrene	affects methylation, decreases methylation	2
Ozone	increases oxidation, increases abundance, affects cotreatment, increases expression	2
Silicon Dioxide	increases expression	2
Particulate Matter	decreases reaction, increases expression	2
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases expression, increases oxidation, increases abundance	1
nickel chloride	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
azoxystrobin	decreases expression	1
CGP 52608	affects binding, increases reaction	1
corosolic acid	increases expression	1
monomethylarsonous acid	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
ICG 001	increases expression	1
abrine	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	increases expression, decreases reaction	1
pyrachlostrobin	decreases expression	1
picoxystrobin	decreases expression	1
(+)-JQ1 compound	decreases expression	1
1-(2-chlorobenzyl)-5’-phenyl-3’H-spiro(indoline-3,2’-(1,3,4)thiadiazol)-2-one	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Resveratrol	increases expression	1
Sunitinib	increases expression	1
Zoledronic Acid	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2J6	Abcam HeLa TNIP1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00120887	PHASE4	COMPLETED	Lupus Atherosclerosis Prevention Study
NCT00125307	PHASE4	COMPLETED	Tacrolimus for the Treatment of Systemic Lupus Erythematosus With Membranous Nephritis
NCT00188188	PHASE4	UNKNOWN	Study of Endothelial Dysfunction in Systemic Lupus and Its Role in Heart Disease
NCT00371501	PHASE4	COMPLETED	Aspirin and Statins for Prevention of Atherosclerosis and Arterial Thromboembolism in Systemic Lupus Erythematosus
NCT00392093	PHASE4	COMPLETED	Effect of Hormone Replacement Therapy on Lupus Activity
NCT00413361	PHASE4	COMPLETED	The Reduction of Systemic Lupus Erythematosus Flares :Study PLUS
NCT00508898	PHASE4	WITHDRAWN	The Efficacy and Safety of Calcitriol for the Treatment of Lupus Nephritis and Persistent Proteinuria
NCT00668330	PHASE4	COMPLETED	Steroid Induced Osteoporosis in Patients With Systemic Lupus Erythematosus
NCT00739050	PHASE4	TERMINATED	Effect of Simvastatin on Endothelial Function in Premenopausal Women With Systemic Lupus Erythematosus (0733-271)(TERMINATED)
NCT00815282	PHASE4	COMPLETED	Immune Response After Human Papillomavirus Vaccination in Patients With Autoimmune Disease
NCT00828178	PHASE4	COMPLETED	Efficacy of Fish Oil in Lupus Patients
NCT00866229	PHASE4	UNKNOWN	Efficacy and Adverse Effect of Simvastatin Compare to Rosuvastatin in Systemic Lupus Erythematosus (SLE) Patients With Corticosteroid Therapy and High Low-Density Lipoprotein (LDL) Cholesterol Level
NCT00911521	PHASE4	COMPLETED	Immunogenicity and Safety of a Quadrivalent Human Papillomavirus (HPV) Vaccine in Patients With SLE: a Controlled Study
NCT01101802	PHASE4	COMPLETED	Mycophenolate Mofetil in Systemic Lupus Erythematosus (MISSILE)
NCT01112215	PHASE4	COMPLETED	Enteric-coated Mycophenolate Sodium Versus Azathioprine for the Extra-renal Lupus Manifestations
NCT01151644	PHASE4	UNKNOWN	Safety and Efficacy of Anti-Pandemic H1N1 Vaccination in Rheumatic Diseases
NCT01276782	PHASE4	WITHDRAWN	Levothyroxine in Pregnant SLE Patients
NCT01322308	PHASE4	COMPLETED	Effect of Pioglitazone on Endothelial Function in Premenopausal Women With Uncomplicated Systemic Lupus Erythematosus
NCT01359826	PHASE4	WITHDRAWN	The Effect of Milnacipran on Fatigue and Quality of Life in Lupus Patients
NCT01597492	PHASE4	COMPLETED	A Study to Evaluate the Effect of Belimumab on Vaccine Responses in Subjects With Systemic Lupus Erythematosus (SLE)
NCT01632241	PHASE4	COMPLETED	Efficacy and Safety of Belimumab in Black Race Patients With Systemic Lupus Erythematosus (SLE)
NCT01705977	PHASE4	COMPLETED	Belimumab Assessment of Safety in SLE
NCT01753401	PHASE4	COMPLETED	Acthar for the Treatment of Systemic Lupus Erythematosus (SLE) in Patients With a History of Persistently Active Disease
NCT02270970	PHASE4	UNKNOWN	Evaluation of Belimumab Impact on a BLyS Activity Signature Test in the Absence of Confounding Polypharmacy
NCT02477150	PHASE4	COMPLETED	Safety and Immunogenicity of a Zoster Vaccine in SLE
NCT02741960	PHASE4	COMPLETED	The Effect of Metformin on Reducing Lupus Flares
NCT02779153	PHASE4	WITHDRAWN	Acthar SLE (Systemic Lupus Erythematosus)
NCT02953821	PHASE4	COMPLETED	Acthar Gel for Active Systemic Lupus Erythematosus (SLE)
NCT03042260	PHASE4	UNKNOWN	Prophylactic Trimethoprim/Sulfamethoxazole to Prevent Severe Infections in Patients With Lupus Erythematous
NCT03098823	PHASE4	COMPLETED	A Crossover Study to Compare RAYOS to IR Prednisone to Improve Fatigue and Morning Symptoms for SLE
NCT03122431	PHASE4	COMPLETED	Relevance of Monitoring Blood and Salivar Levels of Drugs Used in Rheumatic Autoimmune Diseases
NCT03543839	PHASE4	RECRUITING	Trial of Belimumab in Early Lupus
NCT04447053	PHASE4	UNKNOWN	Sequential Belimumab and T-cell Based Therapy in SLE
NCT04515719	PHASE4	COMPLETED	Efficacy and Safety of Belimumab in SLE Patients
NCT04893161	PHASE4	UNKNOWN	A Model About the Response of Belimumab in SLE
NCT04908865	PHASE4	COMPLETED	Open-label Study of Belimumab Plus Standard Therapy in Chinese Pediatric Participants With Active Systemic Lupus Erythematosus (SLE)
NCT04956484	PHASE4	COMPLETED	Belimumab In Early Systemic Lupus Erythematosus
NCT05559671	PHASE4	RECRUITING	Safety of the Herpes Zoster Subunit Vaccine in Lupus
NCT05666336	PHASE4	UNKNOWN	Multi-omics Studies on the Efficacy of Telitacicept in Chinese SLE Patients
NCT05748925	PHASE4	COMPLETED	Cardio Renal Effects of SGLT2 Inhibitors Among Lupus Nephritis Patients