TNFAIP6

Summary

TNFAIP6 (TNF alpha induced protein 6, HGNC:11898) is a protein-coding gene on chromosome 2q23.3, encoding Tumor necrosis factor-inducible gene 6 protein (P98066). Major regulator of extracellular matrix organization during tissue remodeling.

The protein encoded by this gene is a secretory protein that contains a hyaluronan-binding domain, and thus is a member of the hyaluronan-binding protein family. The hyaluronan-binding domain is known to be involved in extracellular matrix stability and cell migration. This protein has been shown to form a stable complex with inter-alpha-inhibitor (I alpha I), and thus enhance the serine protease inhibitory activity of I alpha I, which is important in the protease network associated with inflammation. This gene can be induced by proinflammatory cytokines such as tumor necrosis factor alpha and interleukin-1. Enhanced levels of this protein are found in the synovial fluid of patients with osteoarthritis and rheumatoid arthritis.

Source: NCBI Gene 7130 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 9 total
• MANE Select transcript: NM_007115

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11898
Approved symbol	TNFAIP6
Name	TNF alpha induced protein 6
Location	2q23.3
Locus type	gene with protein product
Status	Approved
Aliases	TSG6, TSG-6
Ensembl gene	ENSG00000123610
Ensembl biotype	protein_coding
OMIM	600410
Entrez	7130

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 retained_intron

ENST00000243347, ENST00000460812

RefSeq mRNA: 1 — MANE Select: NM_007115 NM_007115

CCDS: CCDS2193

Canonical transcript exons

ENST00000243347 — 6 exons

Exon	Start	End
ENSE00000840475	151357592	151357760
ENSE00000840476	151363943	151364080
ENSE00000840477	151366056	151366217
ENSE00000840479	151373549	151373589
ENSE00001217763	151379364	151380046
ENSE00003557441	151370020	151370248

Expression profiles

Bgee: expression breadth ubiquitous, 234 present calls, max score 98.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 78.5551 / max 7399.1406, expressed in 1021 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
23044	78.5551	1021

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cartilage tissue	UBERON:0002418	98.87	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	96.13	gold quality
vena cava	UBERON:0004087	94.20	gold quality
buccal mucosa cell	CL:0002336	92.73	gold quality
sperm	CL:0000019	92.39	gold quality
periodontal ligament	UBERON:0008266	91.89	gold quality
male germ cell	CL:0000015	90.55	gold quality
layer of synovial tissue	UBERON:0007616	90.20	gold quality
synovial joint	UBERON:0002217	89.75	gold quality
calcaneal tendon	UBERON:0003701	89.75	gold quality
blood	UBERON:0000178	89.64	gold quality
trabecular bone tissue	UBERON:0002483	89.33	gold quality
stromal cell of endometrium	CL:0002255	88.09	gold quality
tendon of biceps brachii	UBERON:0008188	87.81	gold quality
gall bladder	UBERON:0002110	87.73	gold quality
tendon	UBERON:0000043	86.87	gold quality
bone element	UBERON:0001474	84.46	gold quality
islet of Langerhans	UBERON:0000006	83.77	gold quality
bone marrow	UBERON:0002371	83.33	gold quality
mucosa of stomach	UBERON:0001199	82.11	gold quality
vermiform appendix	UBERON:0001154	81.54	gold quality
right testis	UBERON:0004534	81.41	gold quality
left testis	UBERON:0004533	81.38	gold quality
mammary duct	UBERON:0001765	81.18	gold quality
skin of hip	UBERON:0001554	81.17	gold quality
smooth muscle tissue	UBERON:0001135	80.83	gold quality
mucosa of urinary bladder	UBERON:0001259	80.68	gold quality
tibia	UBERON:0000979	79.84	gold quality
testis	UBERON:0000473	79.61	gold quality
epithelium of mammary gland	UBERON:0003244	79.43	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-MTAB-8142	yes	17768.69
E-GEOD-98556	yes	538.95
E-HCAD-31	yes	24.22
E-HCAD-4	yes	19.79
E-MTAB-5061	yes	11.94
E-GEOD-83139	yes	7.06
E-ENAD-27	yes	6.93
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CEBPB, CEBPD, FOS, GLI1, JUN, PITX3, RUNX1, RUNX2

miRNA regulators (miRDB)

54 targeting TNFAIP6, 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-5692A	100.00	74.40	6850
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-5580-3P	99.70	69.41	2052
HSA-MIR-5700	99.64	69.88	2280
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-2053	99.57	69.15	1635
HSA-MIR-105-5P	99.54	69.24	2060

Literature-anchored findings (GeneRIF, showing 40)

• polymorphism in osteoarthritis; chromosome location given here (chromosome 2) (PMID:11854277)
• TSG-6 is a multifunctional protein associated with inflammation [review] (PMID:12692188)
• Tumor necrosis factor, alpha-induced protein 6 activates an anti-inflammatory agent- inter-alpha-inhibitor[review]. (PMID:14515153)
• The TSG-6 and I alpha I interaction promotes a transesterification cleaving the protein-glycosaminoglycan-protein (PGP) cross-link. (PMID:15653696)
• This TSG-6 model reveals the residues most likely to be involved in stabilizing the inter-Link module interface, which are highly conserved across the Link protein/ chondroitin sulfate proteoglycan subfamily. (PMID:15718240)
• TSG-6 treatment also resulted in a rapid increase in cyclooxygenase-2 (COX-2) mRNA levels, suggesting that TSG-6 up-regulates COX-2 gene expression (PMID:15809059)
• TSG-6 acts as cofactor and catalyst in the production of IalphaI heavy chain x hyaluronan complexes (PMID:15840581)
• heparin with the Link module significantly increases the anti-plasmin activity of the TSG-6.IalphaI complex; TSG-6 is likely to contribute to matrix remodeling, at least in part, through down-regulation of the protease network (PMID:15917224)
• Results suggest a physiological function of thrombospondin-1 binding to TSG-6 in regulation of hyaluronan metabolism at sites of inflammation. (PMID:16006654)
• The tumor necrosis factor alpha induced protein 6 is a potential marker that could be used for early diagnosis and prognosis of cancerous or precancerous lesions. (PMID:16467113)
• hyaluronan synthase 2 and TSG-6 have roles in hyaluronan distribution and function in proximal tubular epithelial cells (PMID:16687630)
• Evidence is cited in this review that TSG-6 can regulate the expression of various molecules that have important roles in the control of inflammation. (PMID:16709183)
• TSG-6 is down-regulated during osteoblastic differentiation, and suppressed osteoblastic differentiation induced by both BMP-2 and osteogenic differentiation medium. (PMID:16771708)
• TSG-6 may play an important protective role in bronchial epithelium by increasing the antiprotease screen on the airway lumen. (PMID:16873769)
• Crystallography data on the free protein, and (15)N NMR relaxation data for the uncomplexed and HA(8)-bound forms of Link_TSG6, is presented. (PMID:17585936)
• TSG-6 is a high affinity ligand that can mediate fibronectin interactions with other matrix components and modulate some interactions of fibronectin with cells (PMID:18042364)
• 3 genes were upregulated in patients with chronic EBV infection: guanylate binding protein 1, tumor necrosis factor-induced protein 6, and guanylate binding protein 5; they may be associated with the inflammatory reaction or with cell proliferation. (PMID:18260761)
• The transfer of heavy chains from bikunin proteins to hyaluronan requires both TSG-6 and HC2. (PMID:18448433)
• TSG-6 has dual roles in bone remodeling: it inhibits RANKL-induced bone erosion in inflammatory diseases, and its interactions with BMP-2 and RANKL help to balance mineralization by osteoblasts and bone resorption by osteoclasts (PMID:18586671)
• TSG-6 transfers proteins between glycosaminoglycans via a Ser28-mediated covalent catalytic mechanism (PMID:18820257)
• up-regulation in human colorectal cancer is correlated with upregulation of the TIMP-1 transcript (PMID:19383344)
• myelomonocytic cells and MoDC are a major source of TSG-6 and that PTX3 and TSG-6 are coregulated (PMID:19389798)
• TSG-6/HC2 link heavy chains randomly on the chondroitin sulfate chain of bikunin, in contrast to the ordered attachment observed during the biosynthesis. (PMID:20463016)
• negative correlation between TSG-6 expression levels and severity of capsular contracture (CC) suggests a possible protective role for TSG-6 in the context of CC formation, and this may have a clinically relevant role in prevention of breast CC (PMID:21239672)
• TSG-6 protein, a negative regulator of inflammatory arthritis, forms a ternary complex with murine mast cell tryptases and heparin. (PMID:21566135)
• TSG-6 expression by hMSCs was induced 12 h after oropharyngeal delivery to LPS-exposed lungs. Knockdown of TSG-6 expression in hMSCs by RNA interference abrogated most of their anti-inflammatory effects. (PMID:21569482)
• TSG-6 is a potent HA cross-linking agent (PMID:21596748)
• TSG-6 was central to EMT through effects on HA macromolecular structure and through CD44-dependent triggering of cell responses. (PMID:21864707)
• TSG-6 reverts the inhibitory effects exerted by PTX3 on FGF2-mediated angiogenesis through competition of FGF2/PTX3 interaction. (PMID:22267482)
• This review discusses TSG-6 as a potential molecular marker of oocyte maturation. (PMID:22922154)
• The protein product of tumor necrosis factor-alpha stimulated gene-6 strongly correlated with ossification markers and hyaluronidase in calcified human aortic valves. (PMID:23017666)
• TSG-6 increases the accumulation of HA in the cell-associated matrix, partially by preventing its dissolution from the cell-associated matrix into the conditioned medium, but primarily by inducing HA synthesis (PMID:23129777)
• analysis of irreversible heavy chain transfer to hyaluronan oligosaccharides by tumor necrosis factor-stimulated gene-6 (PMID:23166324)
• This study provides insight into what we believe to be a previously undescribed multifaceted role of mesenchymal stem cell-released TSG-6 in wound healing. (PMID:23921952)
• Data indicate that TSG-6-mediated cross-linking of hyaluronan (HA) films is impaired in the presence of inter-alpha-inhibitor (IalphaI) and that this effect suppresses the TSG-6-mediated enhancement of HA binding to CD44-positive cells. (PMID:24005673)
• data suggest that TSG-6 expression might be essential in endometrial matrix organization and feto-maternal communication during the implantation process. (PMID:24213015)
• the HA-binding site defined here may not play a role in TSG-6-mediated transfer of heavy chains from inter-alpha-inhibitor onto HA, a process known to be essential for ovulation. (PMID:24403066)
• TSG-6 suppresses CXCL8-mediated chemotaxis of neutrophils; this lower potency effect might be important at sites where there is high local expression of TSG-6. (PMID:24501198)
• TSG-6 activity in tissues, was examined. (PMID:25325979)
• results suggest that systemic administration of hASC or TSG-6 may be novel approaches to reverse CS-induced myelosuppression. (PMID:25329668)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tnfaip6	ENSDARG00000093440
mus_musculus	Tnfaip6	ENSMUSG00000053475
rattus_norvegicus	Tnfaip6	ENSRNOG00000050792

Paralogs (2): STAB1 (ENSG00000010327), STAB2 (ENSG00000136011)

Protein

Protein identifiers

Tumor necrosis factor-inducible gene 6 protein — P98066 (reviewed: P98066)

Alternative names: Hyaluronate-binding protein, TNF-stimulated gene 6 protein, Tumor necrosis factor alpha-induced protein 6

All UniProt accessions (1): P98066

UniProt curated annotations — full annotation on UniProt →

Function. Major regulator of extracellular matrix organization during tissue remodeling. Catalyzes the transfer of a heavy chain (HC) from inter-alpha-inhibitor (I-alpha-I) complex to hyaluronan. Cleaves the ester bond between the C-terminus of the HC and GalNAc residue of the chondroitin sulfate chain in I-alpha-I complex followed by transesterification of the HC to hyaluronan. In the process, potentiates the antiprotease function of I-alpha-I complex through release of free bikunin. Acts as a catalyst in the formation of hyaluronan-HC oligomers and hyaluronan-rich matrix surrounding the cumulus cell-oocyte complex, a necessary step for oocyte fertilization. Assembles hyaluronan in pericellular matrices that serve as platforms for receptor clustering and signaling. Enables binding of hyaluronan deposited on the surface of macrophages to LYVE1 on lymphatic endothelium and facilitates macrophage extravasation. Alters hyaluronan binding to functionally latent CD44 on vascular endothelium, switching CD44 into an active state that supports leukocyte rolling. Modulates the interaction of chemokines with extracellular matrix components and proteoglycans on endothelial cell surface, likely preventing chemokine gradient formation. In a negative feedback mechanism, may limit excessive neutrophil recruitment at inflammatory sites by antagonizing the association of CXCL8 with glycosaminoglycans on vascular endothelium. Has a role in osteogenesis and bone remodeling. Inhibits BMP2-dependent differentiation of mesenchymal stem cell to osteoblasts. Protects against bone erosion during inflammation by inhibiting TNFSF11/RANKL-dependent osteoclast activation.

Subunit / interactions. Interacts (via Link domain) with inter-alpha-inhibitor (I-alpha-I) component bikunin. Interacts with ITIH2/HC2; this interaction is required for transesterification of the HC to hyaluronan. Interacts (via Link and CUB domains) with ITIH1. Chondroitin sulfate may be required for the stability of the complex. Interacts (via Link domain) with various C-X-C and C-C chemokines including PF4, CXCL8, CXCL11, CXCL12, CCL2, CCL7, CCL19, CCL21, and CCL27; this interaction interferes with chemokine binding to glycosaminoglycans. Interacts (primarily via Link domain) with BMP2; this interaction is inhibited by hyaluronan. Interacts (via both Link and CUB domains) with TNFSF11. Interacts (via CUB domain) with FN1 (via type III repeats 9-14); this interaction enhances fibronectin fibril assembly. TNFAIP6 may act as a bridging molecule between FN1 and THBS1.

Subcellular location. Secreted.

Tissue specificity. Expressed in airway epithelium and submucosal gland (at protein level). Colocalizes with bikunin at the ciliary border. Present in bronchoalveolar lavage fluid (at protein level). Expressed in mesenchymal stem cells. Found in the synovial fluid of patients with rheumatoid arthritis.

Post-translational modifications. N-glycosylated.

Domain organisation. The Link domain interacts with various extracellular matrix components, including heparin, heparan sulfates, hyaluronan and I-alpha-I complex. It is required for binding to various chemokines. The CUB domain is necessary for calcium ion binding and transesterification reaction. It is required for binding to FN1.

Induction. Up-regulated in peripheral blood mononuclear cells, high endothelial venules, airway epithelium and submucosal gland in response to inflammatory cytokine TNF. Down-regulated upon differentiation of mesenchymal stem cells to osteoblasts.

RefSeq proteins (1): NP_009046* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000538	Link_dom	Domain
IPR000859	CUB_dom	Domain
IPR016186	C-type_lectin-like/link_sf	Homologous_superfamily
IPR016187	CTDL_fold	Homologous_superfamily
IPR035914	Sperma_CUB_dom_sf	Homologous_superfamily
IPR052129	Spermadhesin-Link_domain	Family

Pfam: PF00193, PF00431

UniProt features (50 total): strand 15, mutagenesis site 14, binding site 5, disulfide bond 4, helix 3, glycosylation site 2, domain 2, turn 2, signal peptide 1, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
2PF5	X-RAY DIFFRACTION	1.9
2WNO	X-RAY DIFFRACTION	2.3
1O7B	SOLUTION NMR
1O7C	SOLUTION NMR
2N40	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P98066-F1	81.13	0.54

Functional residue map

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

Ligand- & substrate-binding residues (5): 183; 191; 232; 234; 235

Disulfide bonds (4): 58–127, 82–103, 135–161, 188–210

Glycosylation sites (2): 258, 118

Mutagenesis-validated functional residues (14):

Position	Phenotype
39	decreases binding of hyaluronan to cd44. decreases hyaluronan-dependent lymphocyte rolling.
41	has no significant effect on hyaluronan binding to cd44 or hyaluronan-dependent lymphocyte rolling.
46	abolishes binding to bikunin.
47	abolishes binding to bikunin. impairs binding to hyaluronan. retains the ability to bind heavy chains but cannot transfe
48	decreases binding of hyaluronan to cd44. decreases hyaluronan-dependent lymphocyte rolling.
55	decreases binding to heparin. has normal binding to bikunin. impairs binding to heparin; when associated with a-69 and a
64	increases binding of hyaluronan to cd44. has no significant effect on hyaluronan-dependent lymphocyte rolling.
69	decreases binding to heparin. has normal binding to bikunin. impairs binding to heparin; when associated with a-55 and a
76	decreases binding to heparin. has normal binding to bikunin. impairs binding to heparin and decreases the potentiation e
89	decreases binding to heparin. has normal binding to bikunin.
94	abolishes binding to bikunin. has no effect on transesterification reaction.
105	impairs binding of hyaluronan to cd44. decreases hyaluronan-dependent lymphocyte rolling.
113	abolishes binding to bikunin. impairs binding of hyaluronan to cd44. decreases hyaluronan-dependent lymphocyte rolling.
183	reduces the binding affinity to calcium ions. abolishes the interaction with heavy chain itih1.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation

MSigDB gene sets: 408 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GSE45365_NK_CELL_VS_BCELL_UP, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, MCLACHLAN_DENTAL_CARIES_UP, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, GOBP_INFLAMMATORY_RESPONSE, BROWNE_HCMV_INFECTION_8HR_UP, GOCC_SECRETORY_GRANULE, MODULE_45, GOBP_GROWTH, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION

GO Biological Process (14): ovarian cumulus expansion (GO:0001550), inflammatory response (GO:0006954), cell adhesion (GO:0007155), signal transduction (GO:0007165), cell-cell signaling (GO:0007267), hyaluronan metabolic process (GO:0030212), positive regulation of cell migration (GO:0030335), negative regulation of BMP signaling pathway (GO:0030514), negative regulation of osteoblast differentiation (GO:0045668), negative regulation of osteoclast differentiation (GO:0045671), negative regulation of inflammatory response (GO:0050728), negative regulation of neutrophil chemotaxis (GO:0090024), positive regulation of receptor clustering (GO:1903911), fibronectin fibril organization (GO:1905590)

GO Molecular Function (7): fibronectin binding (GO:0001968), calcium ion binding (GO:0005509), hyaluronic acid binding (GO:0005540), carboxylesterase activity (GO:0106435), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), tertiary granule lumen (GO:1904724), ficolin-1-rich granule lumen (GO:1904813)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	2
cell communication	2
signaling	2
intracellular organelle lumen	2
antral ovarian follicle growth	1
ovulation cycle process	1
fused antrum stage	1
developmental growth	1
defense response	1
regulation of cellular process	1
cellular response to stimulus	1
glycosaminoglycan metabolic process	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
BMP signaling pathway	1
regulation of BMP signaling pathway	1
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
negative regulation of cellular response to growth factor stimulus	1
osteoblast differentiation	1
negative regulation of cell differentiation	1
regulation of osteoblast differentiation	1
negative regulation of myeloid leukocyte differentiation	1
osteoclast differentiation	1
regulation of osteoclast differentiation	1
inflammatory response	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of inflammatory response	1
neutrophil chemotaxis	1
negative regulation of granulocyte chemotaxis	1
regulation of neutrophil chemotaxis	1
negative regulation of neutrophil migration	1
receptor clustering	1
regulation of receptor clustering	1
positive regulation of protein localization to membrane	1
supramolecular fiber organization	1
protein binding	1
metal ion binding	1
carboxylic acid binding	1

Protein interactions and networks

STRING

2274 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNFAIP6	PTX3	P26022	950
TNFAIP6	CD44	P16070	947
TNFAIP6	CXCL8	P10145	867
TNFAIP6	THBS1	P07996	827
TNFAIP6	ACAN	P16112	793
TNFAIP6	HAS2	Q92819	771
TNFAIP6	VCAN	P13611	747
TNFAIP6	FN1	P02751	736
TNFAIP6	FRZB	Q92765	714
TNFAIP6	IL1B	P01584	696
TNFAIP6	AMBP	P00977	672
TNFAIP6	IL1A	P01583	666
TNFAIP6	IDO1	P14902	664
TNFAIP6	ITIH5	Q86UX2	660
TNFAIP6	FGF2	P09038	644

IntAct

75 interactions, top by confidence:

A	B	Type	Score
FGF2	PTX3	psi-mi:“MI:0407”(direct interaction)	0.790
FGF2	PTX3	psi-mi:“MI:0915”(physical association)	0.790
THBS1	FN1	psi-mi:“MI:0915”(physical association)	0.610
TNFAIP6	CXCL8	psi-mi:“MI:0407”(direct interaction)	0.560
CXCL8	TNFAIP6	psi-mi:“MI:0407”(direct interaction)	0.560
TNFAIP6	GDF6	psi-mi:“MI:0407”(direct interaction)	0.560
TNFAIP6	BMP2	psi-mi:“MI:0407”(direct interaction)	0.560
TNFAIP6	GDF5	psi-mi:“MI:0407”(direct interaction)	0.560
TNFAIP6	TNFSF11	psi-mi:“MI:0407”(direct interaction)	0.560
TNFAIP6	PTX3	psi-mi:“MI:0407”(direct interaction)	0.560

BioGRID (27): ACAN (Reconstituted Complex), THOC5 (Affinity Capture-MS), LRP2 (Affinity Capture-MS), THOC1 (Affinity Capture-MS), C17orf75 (Affinity Capture-MS), ZMYM6 (Affinity Capture-MS), ACADL (Affinity Capture-MS), KCTD21 (Affinity Capture-MS), THOC7 (Affinity Capture-MS), FAM91A1 (Affinity Capture-MS), TXNDC16 (Affinity Capture-MS), FOXRED2 (Affinity Capture-MS), VCAN (Affinity Capture-MS), KIF7 (Affinity Capture-MS), ITIH3 (Affinity Capture-MS)

ESM2 similar proteins: O08859, O14786, O15072, O54991, P00736, P00751, P04186, P09871, P15156, P28824, P28825, P58397, P78357, P79331, P79795, P97333, P97846, P97857, P98065, P98066, Q03710, Q0V8S9, Q0V8T0, Q0VCX1, Q16819, Q4R577, Q5R1W3, Q5R544, Q5RD64, Q61847, Q64230, Q69DK8, Q6P6T1, Q864V9, Q864W0, Q864W1, Q8C9W3, Q8CFG8, Q8CFG9, Q8CG14

Diamond homologs: A0A182C2Z2, A6QLU6, B7ZCC9, C6K2K4, C6KFA3, F1RWC3, G5E8Q8, G5ECX0, G5EDW2, O08859, O14786, O35276, O35375, O43897, O57382, O57460, O60462, O60494, O70244, O75074, O88204, O88917, O94910, O95490, O97817, O97827, O97831, P13497, P25723, P42664, P42674, P48740, P56677, P97333, P98063, P98064, P98065, P98066, P98068, P98069

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
CEBPB	“up-regulates quantity by expression”	TNFAIP6	“transcriptional regulation”
CEBPD	“up-regulates quantity by expression”	TNFAIP6	“transcriptional regulation”
JUN	“up-regulates quantity by expression”	TNFAIP6	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 26 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
Chemokine receptors bind chemokines	10	89.2×	4e-16
Molecules associated with elastic fibres	5	73.5×	3e-07
Peptide ligand-binding receptors	8	28.2×	1e-08
Class A/1 (Rhodopsin-like receptors)	7	24.7×	3e-07
GPCR ligand binding	7	21.4×	5e-07
G alpha (i) signalling events	8	14.8×	6e-07
Signaling by GPCR	7	13.4×	1e-05
GPCR downstream signalling	5	10.3×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
eosinophil chemotaxis	5	140.9×	2e-08
monocyte chemotaxis	5	111.8×	4e-08
positive regulation of SMAD protein signal transduction	7	103.1×	1e-10
chemokine-mediated signaling pathway	7	87.2×	2e-10
BMP signaling pathway	7	54.0×	4e-09
positive regulation of neuron differentiation	7	53.4×	4e-09
antimicrobial humoral immune response mediated by antimicrobial peptide	8	49.9×	4e-10
positive regulation of osteoblast differentiation	5	43.2×	4e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	6
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

598 predictions. Top by Δscore:

Variant	Effect	Δscore
2:151366052:GCAG:G	acceptor_loss	1.0000
2:151366053:CAGG:C	acceptor_loss	1.0000
2:151366054:A:AG	acceptor_gain	1.0000
2:151366054:AG:A	acceptor_gain	1.0000
2:151366055:G:GA	acceptor_gain	1.0000
2:151366055:GG:G	acceptor_gain	1.0000
2:151366055:GGA:G	acceptor_gain	1.0000
2:151366055:GGAT:G	acceptor_gain	1.0000
2:151370016:TCA:T	acceptor_loss	1.0000
2:151370017:CAG:C	acceptor_loss	1.0000
2:151370018:A:AG	acceptor_gain	1.0000
2:151370018:A:AT	acceptor_loss	1.0000
2:151370019:G:GA	acceptor_gain	1.0000
2:151370019:GC:G	acceptor_gain	1.0000
2:151370019:GCA:G	acceptor_gain	1.0000
2:151370019:GCAA:G	acceptor_gain	1.0000
2:151370019:GCAAA:G	acceptor_gain	1.0000
2:151370244:GGAAG:G	donor_gain	1.0000
2:151370245:GAAG:G	donor_gain	1.0000
2:151370245:GAAGG:G	donor_gain	1.0000
2:151370246:AAGG:A	donor_loss	1.0000
2:151370247:AGGTA:A	donor_loss	1.0000
2:151370249:G:GG	donor_gain	1.0000
2:151370249:GTA:G	donor_loss	1.0000
2:151370250:T:G	donor_loss	1.0000
2:151373590:G:A	donor_loss	1.0000
2:151373590:G:GG	donor_gain	1.0000
2:151357756:GCTTG:G	donor_gain	0.9900
2:151357758:TTGGT:T	donor_loss	0.9900
2:151357759:TGGTA:T	donor_loss	0.9900

AlphaMissense

1831 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:151366192:G:C	W123C	0.999
2:151366192:G:T	W123C	0.999
2:151370106:T:A	C161S	0.999
2:151370106:T:C	C161R	0.999
2:151370107:G:C	C161S	0.999
2:151370114:G:C	W163C	0.999
2:151370114:G:T	W163C	0.999
2:151370149:T:C	L175P	0.999
2:151370197:A:T	D191V	0.999
2:151373583:A:C	S220R	0.999
2:151373585:T:A	S220R	0.999
2:151373585:T:G	S220R	0.999
2:151379385:T:C	F229S	0.999
2:151379417:T:C	F240L	0.999
2:151379418:T:C	F240S	0.999
2:151379418:T:G	F240C	0.999
2:151379419:C:A	F240L	0.999
2:151379419:C:G	F240L	0.999
2:151379429:T:G	Y244D	0.999
2:151370028:T:A	C135S	0.998
2:151370029:G:C	C135S	0.998
2:151370089:A:G	Y155C	0.998
2:151370107:G:A	C161Y	0.998
2:151370108:C:G	C161W	0.998
2:151370196:G:C	D191H	0.998
2:151370203:T:A	V193D	0.998
2:151373553:T:A	C210S	0.998
2:151373554:G:A	C210Y	0.998
2:151373554:G:C	C210S	0.998
2:151379385:T:G	F229C	0.998

dbSNP variants (sampled 300 via entrez): RS1000029443 (2:151361776 C>T), RS1000235943 (2:151381011 G>A), RS1000243544 (2:151377988 G>A), RS1000443006 (2:151361522 G>A), RS1000883264 (2:151357968 G>A), RS1000892017 (2:151369801 C>A,T), RS1000962247 (2:151370054 G>A), RS1001184219 (2:151362144 T>A), RS1001254547 (2:151362618 G>A), RS1001367138 (2:151355932 C>A,G), RS1001511204 (2:151381754 A>G), RS1001594407 (2:151359421 C>A,T), RS1001741172 (2:151377650 A>C), RS1001777299 (2:151355729 T>C), RS1002186594 (2:151363689 A>T)

Disease associations

OMIM: gene MIM:600410 | 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
GCST001740_4	Lung cancer	5.000000e-06
GCST006585_138	Blood protein levels	7.000000e-132

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects expression, increases abundance, increases expression, decreases expression	4
Lipopolysaccharides	affects cotreatment, increases expression, affects response to substance	4
Estradiol	decreases reaction, increases expression, affects cotreatment, decreases expression	3
Asbestos, Crocidolite	increases expression	3
Particulate Matter	increases abundance, increases expression, decreases expression	3
sodium arsenite	decreases expression	2
nickel sulfate	increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases activity, decreases reaction, increases expression	2
Troglitazone	increases expression	2
Aspirin	decreases expression, increases expression	2
Atrazine	affects cotreatment, increases expression, decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Drugs, Chinese Herbal	increases expression	2
Eugenol	increases expression	2
Hyaluronic Acid	affects binding, increases reaction	2
Nickel	increases expression	2
Paraquat	decreases reaction, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Progesterone	decreases expression, decreases reaction, increases expression, affects cotreatment	2
Silicon Dioxide	decreases expression, increases expression	2
Tretinoin	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
GSK-J4	increases expression	1
TL8-506	affects cotreatment, increases expression	1
4-(2-aminoethyl)benzenesulfonylfluoride	affects cotreatment, decreases expression, decreases reaction	1
tungsten carbide	affects cotreatment, decreases expression	1
daidzein	affects cotreatment, decreases expression	1
methylmercuric chloride	increases expression	1
propionaldehyde	increases expression	1

Clinical trials (associated diseases)

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