TRAF3IP2

Summary

TRAF3IP2 (TRAF3 interacting protein 2, HGNC:1343) is a protein-coding gene on chromosome 6q21, encoding E3 ubiquitin ligase TRAF3IP2 (O43734). E3 ubiquitin ligase that catalyzes ‘Lys-63’-linked polyubiquitination of target protein, enhancing protein-protein interaction and cell signaling.

This gene encodes a protein involved in regulating responses to cytokines by members of the Rel/NF-kappaB transcription factor family. These factors play a central role in innate immunity in response to pathogens, inflammatory signals and stress. This gene product interacts with TRAF proteins (tumor necrosis factor receptor-associated factors) and either I-kappaB kinase or MAP kinase to activate either NF-kappaB or Jun kinase. Several alternative transcripts encoding different isoforms have been identified. Another transcript, which does not encode a protein and is transcribed in the opposite orientation, has been identified. Overexpression of this transcript has been shown to reduce expression of at least one of the protein encoding transcripts, suggesting it has a regulatory role in the expression of this gene.

Source: NCBI Gene 10758 — RefSeq curated summary.

At a glance

• Gene–disease (curated): candidiasis, familial, 8 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 20
• Clinical variants (ClinVar): 208 total — 12 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 39
• Druggable target: yes
• MANE Select transcript: NM_147686

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1343
Approved symbol	TRAF3IP2
Name	TRAF3 interacting protein 2
Location	6q21
Locus type	gene with protein product
Status	Approved
Aliases	DKFZP586G0522, ACT1, CIKS
Ensembl gene	ENSG00000056972
Ensembl biotype	protein_coding
OMIM	607043
Entrez	10758

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 17 protein_coding, 6 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000340026, ENST00000359831, ENST00000368730, ENST00000368731, ENST00000368734, ENST00000368735, ENST00000368761, ENST00000464903, ENST00000492671, ENST00000528599, ENST00000532708, ENST00000650649, ENST00000651359, ENST00000651547, ENST00000699907, ENST00000699908, ENST00000699909, ENST00000699910, ENST00000699911, ENST00000699912, ENST00000699913, ENST00000907309, ENST00000907310, ENST00000912363, ENST00000945262, ENST00000945263

RefSeq mRNA: 4 — MANE Select: NM_147686 NM_001164281, NM_001164283, NM_147200, NM_147686

CCDS: CCDS5092, CCDS5093, CCDS55049, CCDS55050

Canonical transcript exons

ENST00000368761 — 9 exons

Exon	Start	End
ENSE00001553799	111555381	111559551
ENSE00003591015	111562965	111563039
ENSE00003602455	111575643	111575821
ENSE00003604306	111591258	111592094
ENSE00003646813	111566444	111566560
ENSE00003664795	111580197	111580389
ENSE00003671465	111567624	111567692
ENSE00003714925	111572895	111572983
ENSE00003843544	111605776	111605878

Expression profiles

Bgee: expression breadth ubiquitous, 266 present calls, max score 95.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.2950 / max 171.5249, expressed in 1748 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
75104	14.1219	1724
75106	2.1219	877
75103	1.3303	675
75102	0.6728	316
75105	0.5033	312
75107	0.4995	293
75108	0.4094	241
75101	0.3171	174
75100	0.1408	55
75099	0.1153	50

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cartilage tissue	UBERON:0002418	95.89	gold quality
oocyte	CL:0000023	94.78	gold quality
skin of leg	UBERON:0001511	94.10	gold quality
skin of abdomen	UBERON:0001416	93.67	gold quality
body of uterus	UBERON:0009853	93.65	gold quality
mucosa of transverse colon	UBERON:0004991	93.58	gold quality
lower esophagus mucosa	UBERON:0035834	93.22	gold quality
colonic epithelium	UBERON:0000397	92.84	gold quality
zone of skin	UBERON:0000014	92.56	gold quality
islet of Langerhans	UBERON:0000006	92.54	gold quality
ectocervix	UBERON:0012249	92.28	gold quality
right uterine tube	UBERON:0001302	92.21	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.21	gold quality
endocervix	UBERON:0000458	92.12	gold quality
secondary oocyte	CL:0000655	92.09	gold quality
esophagus mucosa	UBERON:0002469	91.93	gold quality
smooth muscle tissue	UBERON:0001135	91.04	gold quality
body of stomach	UBERON:0001161	91.04	gold quality
minor salivary gland	UBERON:0001830	91.00	gold quality
rectum	UBERON:0001052	90.93	gold quality
tongue squamous epithelium	UBERON:0006919	90.80	silver quality
uterine cervix	UBERON:0000002	90.65	gold quality
mucosa of urinary bladder	UBERON:0001259	90.60	gold quality
omental fat pad	UBERON:0010414	90.58	gold quality
peritoneum	UBERON:0002358	90.56	gold quality
myometrium	UBERON:0001296	90.19	gold quality
uterus	UBERON:0000995	90.13	gold quality
mouth mucosa	UBERON:0003729	90.03	gold quality
pancreas	UBERON:0001264	89.98	gold quality
esophagus	UBERON:0001043	89.97	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CEBPB, CEBPG, HAND2, IRF1

miRNA regulators (miRDB)

149 targeting TRAF3IP2, 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-6867-5P	100.00	82.21	3464
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482

Literature-anchored findings (GeneRIF, showing 40)

• Endogenous Act1 is recruited to the CD40 receptor in human intestinal (HT29) and cervical (HeLa) epithelial cells upon stimulation with CD40 ligand, indicating that Act1 is involved in this signaling pathway. (PMID:12089335)
• Data indicate that the newly identified alternatively spliced Act1 is a major transcript of the molecule and that Act1 may play important roles in oncogenesis. (PMID:12163033)
• CIKS forms homo-oligomers, interacts with NEMO/IKKgamma, and is recruited to the IKK-complex upon cell stimulation (PMID:12943667)
• two independent and indispensable signaling pathways-1) JAK1-associated PI3K signaling and 2) Act1/TRAF6/TAK1-mediated NF-kappaB activation-are stimulated by IL-17A to regulate gene induction in human airway epithelial cells. (PMID:17982039)
• Whereas Act1 interacts with the IL-17R through the C-terminal SEFIR domain, Act1 is recruited to CD40 and BAFFR indirectly, which is mediated by TRAF3 through the TRAF binding site in Act1[review] (PMID:18061473)
• Act1 mediates IL-17-induced signaling pathways through its E3 ubiquitin ligase activity and TRAF6 is a critical substrate of Act1, which indicates the importance of protein ubiquitination in the IL-17-dependent inflammatory response (PMID:19825828)
• Act1 transgene functions as an important regulator of B cell activating factor (BAFF)-mediated survival of transitional B cells and their maturation into follicular and marginal zone B cells. (PMID:20543113)
• TRAF3IP2 represents a shared susceptibility for (PMID:20953188)
• Act-1 contributed to the stimulatory effect of IL-17 on RAGE production in rheumatoid arthritis (PMID:21749686)
• Data indicate that knockdown of beta-TrCP1 and beta-TrCP2 markedly reduced IL-17-induced, phosphorylation-dependent ubiquitination and degradation of Act1. (PMID:22045853)
• our findings suggest that TRAF3IP2 variants contribute to cutaneous extarintestinal manifestations of both Crohn’s disease and ulcerative colitis. (PMID:22445837)
• In psoriatic arthritis patients the TRAF3IP2-variant p.Asp10Asn is the only susceptiblity allele with functional impact on TRAF6 binding. (PMID:22513239)
• A CIKS mutant may promote the initiation of psoriatic inflammation (PMID:22581863)
• The findings define a new role for the IKK-related kinases in suppressing IL-17-mediated NF-kappaB activation through TRAF6-dependent Act1 phosphorylation. (PMID:22851696)
• IL-17 receptor adaptor protein Act1/CIKS plays an evolutionarily conserved role in antiviral signaling. (PMID:23066157)
• Data show the contribution of TRAF3IP2 genetic variability in Systemic lupus erythematosus (SLE) susceptibility. (PMID:23836313)
• Results suggest that Act1 might play a key role in the pathophysiology and the treatment of rheumatoid arthritis. (PMID:23862741)
• Deletion of Act1 in NG2-positive glia results in markedly reduced experimental autoimmune encephalomyelitis in transgenic mice. (PMID:23995070)
• Replicate the association of TRAF3IP2-_rs33980500 variant with the susceptibility to psoriasis. (PMID:24005976)
• Human IL-17A and IL-17F depend on ACT1 to mediate protective mucocutaneous immunity. (PMID:24120361)
• Genetic polymorphism in the TRAF3IP2 gene is associated with psoriasis vulgaris in a Japanese population. (PMID:24373565)
• This study provides evidence that TRAF5 and TRAF3IP2 genes are involved in the development ofBehcet’s disease (BD) and Vogt-Koyanagi-Harada (VKH) syndrome. (PMID:24416204)
• These results indicate that oxLDL-induced endothelial cell death and dysfunction are mediated via TRAF3IP2 and that native HDL3 and the AMPK activators inhibit this response. (PMID:24561578)
• Single nucleotide polymorphisms in RBPJ, IL1R1, REV3L, TRAF3IP2, IRF1 and ICOS showed association with rheumatoid arthritis in black South Africans. (PMID:25014791)
• this study demonstrated that although ACT1-v2-D10N is nonfunctional, ACT1-v1-D19N retains the ability to interact with Hsp90 and is fully responsive to IL-17A stimulation. (PMID:25024377)
• identify Syk as an upstream signaling molecule in IL-17A-induced Act1-TRAF6 interaction in keratinocytes, and inhibition of Syk can attenuate CCL20 production (PMID:25202827)
• A variant (rs76228616 SNP) in TRAF3IP2 gene could be involved in susceptibility to Steven-Johnson Syndrome. (PMID:25775161)
• Both the ACT-1 assay and the MAdCAM-1 assay demonstrated acceptable reproducibility and repeatability. The assays were sufficiently stable to allow for clinical use. During clinical testing the assays demonstrated that vedolizumab was able to saturate peripheral cells at all doses tested. (PMID:25908521)
• TRAF3IP2 may play a causal role in aldosterone-induced adverse cardiac remodeling in vivo. (PMID:26148936)
• The suppressive effects of miR-30a were mediated by directly targeting Traf3ip2 mRNA (PMID:26376209)
• A G/G genotype of rs766748 in IL-17F, and a C/C or C/A genotype of rs1883136 in TRAF3IP2. (PMID:26558270)
• ACT1 is an essential adaptor molecule of Il-17-induced expression of inflammation-related gene targets. (PMID:27660002)
• the first report to describe a non-adaptor function of Act1 by directly binding to the promoter region of IL-17A responsive genes and directly regulate their transcription. (PMID:27723765)
• TRAF3IP2 SNP rs33980500 associated with no achievement of low disease activity nor remission at 6 months (PMID:28107378)
• AP1 binding sites were enriched upstream of genes up-regulated by TRAF3IP2 silencing. Correspondingly, nuclear expression of FosB and Fra1 was increased in TRAF3IP2-silenced cells. Many genes involved in host defense were induced by IL-17 in a TRAF3IP2-dependent fashion. (PMID:28274739)
• Four genes-ACT1, PIN1, DNMT1 and NTN1-emerged as having roles in pathways that may influence Primary Biliary Cholangitis pathogenesis in British Columbia First Nations people. (PMID:29297981)
• Act1 D10N missense mutation impairs CD40L-induced phosphorylation of p65, p38, and Erk in B-cells. (PMID:29302052)
• We also identify a novel LRI site located within the TRAF3IP2-AS1 promoter, 200 kb distant from the TRAF3IP2 promoter, showing genetic association with psoriasis both in our discovery cohort, as well as in the large WTCCC replication cohort. (PMID:30076642)
• Study results implicate neutrophil extracellular traps (NETs) and the T allele of rs33980500 (T/C), a psoriasis risk-associated variant in the TRAF3IP2 gene encoding the D10N variant of Act1, in human Th17 induction from peripheral blood mononuclear cells and verified that the effect of Act1 D10N was greater in the presence of NETs. (PMID:30528823)
• increased MMP-13 and decreased RECK contribute to IL-17A-induced TRAF3IP2-dependent smooth muscle cell migration and proliferation. (PMID:31074012)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Traf3ip2	ENSMUSG00000019842
rattus_norvegicus	Traf3ip2	ENSRNOG00000000595

Protein

Protein identifiers

E3 ubiquitin ligase TRAF3IP2 — O43734 (reviewed: O43734)

Alternative names: Adapter protein CIKS, Connection to IKK and SAPK/JNK, E3 ubiquitin-protein ligase CIKS, Nuclear factor NF-kappa-B activator 1, TRAF3-interacting protein 2

All UniProt accessions (6): O43734, A0A494C0G2, A0A494C0I3, A0A494C0R7, A0A494C1J9, A0A8V8TQD6

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin ligase that catalyzes ‘Lys-63’-linked polyubiquitination of target protein, enhancing protein-protein interaction and cell signaling. Transfers ubiquitin from E2 ubiquitin-conjugating enzyme UBE2V1-UBE2N to substrate protein. Essential adapter molecule in IL17A-mediated signaling. Upon IL17A stimulation, interacts with IL17RA and IL17RC receptor chains through SEFIR domains and catalyzes ‘Lys-63’-linked polyubiquitination of TRAF6, leading to TRAF6-mediated activation of NF-kappa-B and MAPkinase pathways.

Subunit / interactions. Interacts with IKBKG/NF-kappa B essential modulator, with CHUK/IKK-alpha and with IKBKB/IKK-beta. Interacts with TRAF6; this interaction is direct. Interacts with IL17RA and IL17RC. Interacts with IL17RB.

Tissue specificity. Widely expressed.

Disease relevance. Psoriasis 13 (PSORS13) [MIM:614070] A common, chronic inflammatory disease of the skin with multifactorial etiology. It is characterized by red, scaly plaques usually found on the scalp, elbows and knees. These lesions are caused by abnormal keratinocyte proliferation and infiltration of inflammatory cells into the dermis and epidermis. Disease susceptibility is associated with variants affecting the gene represented in this entry. Candidiasis, familial, 8 (CANDF8) [MIM:615527] A primary immunodeficiency disorder with altered immune responses and impaired clearance of fungal infections, selective against Candida. It is characterized by persistent and/or recurrent infections of the skin, nails and mucous membranes caused by organisms of the genus Candida, mainly Candida albicans. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (5)

UniProt ID	Names	Canonical?
O43734-1	1, C6ORF4	yes
O43734-2	2, C6ORF5, C6ORF6
O43734-3	3
O43734-4	4
O43734-5	5

RefSeq proteins (4): NP_001157753, NP_001157755, NP_671733, NP_679211* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013568	SEFIR_dom	Domain
IPR053047	E3_ubiq_ligase_TRAF3IP2	Family

Pfam: PF08357

UniProt features (23 total): splice variant 4, sequence variant 4, mutagenesis site 4, region of interest 4, compositionally biased region 3, sequence conflict 2, chain 1, domain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9OT1	ELECTRON MICROSCOPY	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43734-F1	53.91	0.16

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 (4):

Position	Phenotype
303	loss of e3 ubiquitin ligase activity.
318	decreases e3 ubiquitin ligase activity.
319	loss of e3 ubiquitin ligase activity.
324	decreases e3 ubiquitin ligase activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 421 (showing top): GOBP_B_CELL_HOMEOSTASIS, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_DEFENSE_RESPONSE_TO_VIRUS, GOBP_RESPONSE_TO_PEPTIDE, GOBP_B_CELL_ACTIVATION, GOBP_KERATINOCYTE_PROLIFERATION, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_LYMPHOCYTE_HOMEOSTASIS, GOBP_GROWTH, GOBP_LYMPH_NODE_DEVELOPMENT, GOBP_MACROMOLECULE_CATABOLIC_PROCESS

GO Biological Process (45): establishment of T cell polarity (GO:0001768), B cell homeostasis (GO:0001782), B cell apoptotic process (GO:0001783), kidney development (GO:0001822), positive regulation of defense response to virus by host (GO:0002230), leukocyte activation involved in inflammatory response (GO:0002269), transitional two stage B cell differentiation (GO:0002334), B cell affinity maturation (GO:0002344), eosinophil mediated immunity (GO:0002447), protein import into nucleus (GO:0006606), inflammatory response (GO:0006954), humoral immune response (GO:0006959), heart development (GO:0007507), response to xenobiotic stimulus (GO:0009410), signal transduction involved in regulation of gene expression (GO:0023019), CD40 signaling pathway (GO:0023035), T cell differentiation (GO:0030217), tumor necrosis factor-mediated signaling pathway (GO:0033209), intracellular signal transduction (GO:0035556), interleukin-17A-mediated signaling pathway (GO:0038173), type 2 immune response (GO:0042092), neutrophil activation (GO:0042119), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), skin development (GO:0043588), mRNA stabilization (GO:0048255), lymph node development (GO:0048535), spleen development (GO:0048536), mucus secretion (GO:0070254), protein K63-linked ubiquitination (GO:0070534), T-helper 17 type immune response (GO:0072538), interleukin-17-mediated signaling pathway (GO:0097400), protein localization to P-body (GO:0110012), eosinophil homeostasis (GO:1990959), protein polyubiquitination (GO:0000209), immune response (GO:0006955), gene expression (GO:0010467), protein ubiquitination (GO:0016567), cytokine-mediated signaling pathway (GO:0019221), B cell mediated immunity (GO:0019724), response to cytokine (GO:0034097)

GO Molecular Function (4): signaling receptor binding (GO:0005102), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (5): nucleus (GO:0005634), cytoplasm (GO:0005737), extrinsic component of cytoplasmic side of plasma membrane (GO:0031234), cytoplasmic vesicle (GO:0031410), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
T cell activation	2
animal organ development	2
signal transduction	2
cytokine-mediated signaling pathway	2
intracellular anatomical structure	2
cellular anatomical structure	2
establishment of lymphocyte polarity	1
lymphocyte homeostasis	1
lymphocyte apoptotic process	1
renal system development	1
regulation of defense response to virus by host	1
inflammatory response	1
leukocyte activation	1
transitional stage B cell differentiation	1
peripheral B cell selection	1
immunoglobulin production involved in immunoglobulin-mediated immune response	1
myeloid leukocyte mediated immunity	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
defense response	1
immune response	1
circulatory system development	1
response to chemical	1
regulation of gene expression	1
cell surface receptor signaling pathway	1
lymphocyte differentiation	1
cellular response to tumor necrosis factor	1
protein binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
cytoplasmic side of plasma membrane	1
extrinsic component of plasma membrane	1
cytoplasm	1
intracellular vesicle	1

Protein interactions and networks

STRING

1322 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRAF3IP2	TRAF3	Q13114	969
TRAF3IP2	IL17RA	Q96F46	892
TRAF3IP2	IKBKG	Q9Y6K9	836
TRAF3IP2	IL17RC	Q8NAC3	813
TRAF3IP2	IL17A	Q16552	797
TRAF3IP2	TRAF6	Q9Y4K3	741
TRAF3IP2	TNFAIP3	P21580	728
TRAF3IP2	IKBKB	O14920	698
TRAF3IP2	TRAF5	O00463	673
TRAF3IP2	IL17RB	Q9NRM6	664
TRAF3IP2	TNIP1	Q15025	621
TRAF3IP2	LCE3B	Q5TA77	599
TRAF3IP2	CARD14	Q9BXL6	595
TRAF3IP2	NFKBIZ	Q9BYH8	587
TRAF3IP2	IL23R	Q5VWK5	582

IntAct

39 interactions, top by confidence:

A	B	Type	Score
TRAF6	TRAF3IP2	psi-mi:“MI:0915”(physical association)	0.670
TRAF3IP2	TRAF6	psi-mi:“MI:0915”(physical association)	0.670
QPRT	PIK3C2A	psi-mi:“MI:0914”(association)	0.640
TRIP6	TRAF3IP2	psi-mi:“MI:0915”(physical association)	0.560
RIMBP3	TRAF3IP2	psi-mi:“MI:0915”(physical association)	0.560
TRAF3IP2	STK16	psi-mi:“MI:0915”(physical association)	0.560
TRAF3IP2	MRPL28	psi-mi:“MI:0915”(physical association)	0.560
TRAF3IP2	FHL3	psi-mi:“MI:0915”(physical association)	0.560
TRAF3IP2	TRIP6	psi-mi:“MI:0915”(physical association)	0.560
TRAF3IP2	RIMBP3	psi-mi:“MI:0915”(physical association)	0.560
FHL3	TRAF3IP2	psi-mi:“MI:0915”(physical association)	0.560
Dlg4	TRAF3IP2	psi-mi:“MI:0407”(direct interaction)	0.440
TRAF2	TRAF3IP2	psi-mi:“MI:0915”(physical association)	0.370
MDFI	TRAF3IP2	psi-mi:“MI:0915”(physical association)	0.370
TRAF3IP2	GOLGA2	psi-mi:“MI:0915”(physical association)	0.370
Tube1	RTL8C	psi-mi:“MI:0914”(association)	0.350
Map9	TRAF3IP2	psi-mi:“MI:0914”(association)	0.350
MMGT1	DERL1	psi-mi:“MI:0914”(association)	0.350
INVS	TRAF3IP2	psi-mi:“MI:0914”(association)	0.350

BioGRID (102): TRAF3IP2 (Affinity Capture-Western), SYK (Affinity Capture-Western), IL17RA (Affinity Capture-Western), TRAF3IP2 (Affinity Capture-Western), TRAF6 (Affinity Capture-Western), UBE2V1 (Reconstituted Complex), ELAVL1 (Affinity Capture-Western), TRAF3IP2 (Affinity Capture-Western), SRSF1 (Affinity Capture-Western), TRAF3IP2 (Two-hybrid), TRAF3IP2 (Two-hybrid), TRAF3IP2 (Two-hybrid), TRAF3IP2 (Two-hybrid), TRAF3IP2 (Two-hybrid), RIMBP3 (Two-hybrid)

ESM2 similar proteins: A0JNG6, A2AKB4, A7YWL5, B0BN13, O35181, O43734, O70142, O70240, O88286, O88566, P0DPB3, P0DPB4, P56975, P70298, P86174, P97303, Q00IB7, Q1LY51, Q2M3C6, Q2T9L4, Q3TY60, Q498S6, Q4V7B1, Q568Z1, Q5HZN9, Q5JTD0, Q5SYB0, Q5U5E5, Q5VT97, Q69ZB8, Q6PG95, Q6UXB0, Q6ZU67, Q76N89, Q80YE4, Q86XD5, Q8BWU3, Q8BZB3, Q8CD60, Q8N365

Diamond homologs: O43734, Q8N7N6

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
IKBKE	“up-regulates activity”	TRAF3IP2	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	4
Uncertain significance	86
Likely benign	76
Benign	12

Top pathogenic / likely-pathogenic (16)

Variant ID	HGVS	Classification
1036337	NM_147686.4(TRAF3IP2):c.926_1022+148delinsTGACCTGAAAAGTCTATATTGGGCATTCCACTATGTGACTTGCTCACTAACGTGGGTTAGCAAACCTATAGAGAATTCTGTTACATCTTCATTGCATTGGCATAATTCCTTTCCATGTTAAAAATGCCTGAAGGTTGGGCCTGTCATACTTACTGGTGCCTTGGAAGCCCCGGAAAGGAGCAGTCTCTCTGTGCGGGCCTCTCTTCGTGGTCCCAGGGGCTGGGATAATTCAGGATAACCTTCTGCACAG	Pathogenic
1054010	NM_147686.4(TRAF3IP2):c.1222del (p.Ser408fs)	Pathogenic
2167641	NM_147686.4(TRAF3IP2):c.1471C>T (p.Arg491Ter)	Pathogenic
2414357	NM_147686.4(TRAF3IP2):c.7C>T (p.Arg3Ter)	Pathogenic
3242312	GRCh37/hg19 6q21-22.31(chr6:109324789-124836619)x1	Pathogenic
3616939	NM_147686.4(TRAF3IP2):c.1392del (p.Lys465fs)	Pathogenic
3625944	NM_147686.4(TRAF3IP2):c.973G>T (p.Glu325Ter)	Pathogenic
3718612	NM_147686.4(TRAF3IP2):c.847C>T (p.Arg283Ter)	Pathogenic
4808700	NM_147686.4(TRAF3IP2):c.395C>G (p.Ser132Ter)	Pathogenic
658088	NM_147686.4(TRAF3IP2):c.1044_1084del (p.Pro349fs)	Pathogenic
812084	NM_147686.4(TRAF3IP2):c.1286C>A (p.Thr429Asn)	Pathogenic
88768	NM_147686.4(TRAF3IP2):c.1580C>T (p.Thr527Ile)	Pathogenic
2177771	NM_147686.4(TRAF3IP2):c.1201+1G>C	Likely pathogenic
2787870	NM_147686.4(TRAF3IP2):c.1201+2T>C	Likely pathogenic
3246037	NC_000006.11:g.(?111887655)(111890372_?)del	Likely pathogenic
4746317	NM_147686.4(TRAF3IP2):c.1201+1G>A	Likely pathogenic

SpliceAI

1561 predictions. Top by Δscore:

Variant	Effect	Δscore
6:111566438:ACTC:A	donor_loss	1.0000
6:111566439:CTCA:C	donor_loss	1.0000
6:111566440:T:TA	donor_loss	1.0000
6:111566442:ACCAT:A	donor_loss	1.0000
6:111566443:C:G	donor_loss	1.0000
6:111566443:CCATT:C	donor_gain	1.0000
6:111566462:A:AC	donor_gain	1.0000
6:111566463:G:C	donor_gain	1.0000
6:111566480:AT:A	donor_gain	1.0000
6:111566481:T:TA	donor_gain	1.0000
6:111566556:GTCTT:G	acceptor_gain	1.0000
6:111566558:CTT:C	acceptor_gain	1.0000
6:111566559:TT:T	acceptor_gain	1.0000
6:111566560:TC:T	acceptor_loss	1.0000
6:111566561:C:CC	acceptor_gain	1.0000
6:111566561:C:CG	acceptor_loss	1.0000
6:111566564:T:TC	acceptor_gain	1.0000
6:111566567:A:AC	acceptor_gain	1.0000
6:111566567:A:C	acceptor_gain	1.0000
6:111567618:ACTT:A	donor_loss	1.0000
6:111567619:CTTA:C	donor_loss	1.0000
6:111567620:TT:T	donor_loss	1.0000
6:111567621:TACAT:T	donor_loss	1.0000
6:111567622:A:AC	donor_gain	1.0000
6:111567622:ACAT:A	donor_gain	1.0000
6:111567622:ACATC:A	donor_gain	1.0000
6:111567623:C:A	donor_loss	1.0000
6:111567623:C:CC	donor_gain	1.0000
6:111567623:CA:C	donor_gain	1.0000
6:111567623:CAT:C	donor_gain	1.0000

AlphaMissense

3703 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:111559509:A:G	W541R	1.000
6:111559509:A:T	W541R	1.000
6:111559532:A:G	L533P	1.000
6:111559536:A:G	W532R	1.000
6:111559536:A:T	W532R	1.000
6:111563001:G:C	F514L	1.000
6:111563001:G:T	F514L	1.000
6:111563003:A:G	F514L	1.000
6:111563025:G:C	F506L	1.000
6:111563025:G:T	F506L	1.000
6:111563027:A:G	F506L	1.000
6:111566531:G:C	S472R	1.000
6:111566531:G:T	S472R	1.000
6:111566533:T:G	S472R	1.000
6:111572904:G:C	F436L	1.000
6:111572904:G:T	F436L	1.000
6:111572905:A:G	F436S	1.000
6:111572906:A:G	F436L	1.000
6:111572973:A:C	F413L	1.000
6:111572973:A:T	F413L	1.000
6:111572975:A:G	F413L	1.000
6:111559468:T:A	R554S	0.999
6:111559468:T:G	R554S	0.999
6:111559469:C:A	R554I	0.999
6:111559469:C:G	R554T	0.999
6:111559475:A:G	L552P	0.999
6:111559507:C:A	W541C	0.999
6:111559507:C:G	W541C	0.999
6:111559532:A:T	L533H	0.999
6:111559534:C:A	W532C	0.999

dbSNP variants (sampled 300 via entrez): RS1000062542 (6:111582748 T>C), RS1000141927 (6:111576136 T>C), RS1000214599 (6:111596370 G>A), RS1000253260 (6:111556925 G>A), RS1000437441 (6:111577159 T>G), RS1000439912 (6:111589986 A>G), RS1000490171 (6:111603317 C>T), RS1000547588 (6:111590540 C>T), RS1000556456 (6:111569110 G>T), RS1000561686 (6:111571037 G>C), RS1000616378 (6:111570617 C>G,T), RS1000762338 (6:111570574 T>C), RS1000777534 (6:111603111 CAA>C), RS1000784796 (6:111584982 A>G), RS1000792131 (6:111570221 C>T)

Disease associations

OMIM: gene MIM:607043 | disease phenotypes: MIM:615527, MIM:614070

GenCC curated gene-disease

Disease	Classification	Inheritance
candidiasis, familial, 8	Strong	Autosomal recessive
chronic mucocutaneous candidiasis	Supportive	Autosomal dominant

Mondo (4): candidiasis, familial, 8 (MONDO:0014230), psoriasis 13, susceptibility to (MONDO:0013554), discoid lupus erythematosus (MONDO:0019558), chronic mucocutaneous candidiasis (MONDO:0015279)

Orphanet (2): Chronic mucocutaneous candidiasis (Orphanet:1334), Discoid lupus erythematosus (Orphanet:90281)

HPO phenotypes

39 total (30 of 39 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000142	Abnormal vagina morphology
HP:0000153	Abnormality of the mouth
HP:0000158	Macroglossia
HP:0000159	Abnormal lip morphology
HP:0000478	Abnormality of the eye
HP:0000498	Blepharitis
HP:0000504	Abnormality of vision
HP:0000682	Abnormal dental enamel morphology
HP:0000790	Hematuria
HP:0000951	Abnormality of the skin
HP:0000962	Hyperkeratosis
HP:0000988	Skin rash
HP:0000989	Pruritus
HP:0001051	Seborrheic dermatitis
HP:0001231	Abnormal fingernail morphology
HP:0001250	Seizure
HP:0001597	Abnormal nail morphology
HP:0001821	Broad nail
HP:0002105	Hemoptysis
HP:0002205	Recurrent respiratory infections
HP:0002715	Abnormality of the immune system
HP:0002719	Recurrent infections
HP:0003621	Juvenile onset
HP:0004306	Abnormal endocardium morphology
HP:0004370	Abnormality of temperature regulation
HP:0008388	Abnormal toenail morphology
HP:0008872	Feeding difficulties in infancy
HP:0009098	Chronic oral candidiasis

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST000833_14	Psoriasis	2.000000e-16
GCST000833_5	Psoriasis	5.000000e-20
GCST000835_3	Psoriatic arthritis	1.000000e-20
GCST000836_2	Psoriasis	1.000000e-16
GCST001725_23	Inflammatory bowel disease	1.000000e-13
GCST002738_15	Psoriasis	1.000000e-14
GCST002740_47	Inflammatory skin disease	1.000000e-26
GCST002874_55	Psoriasis	1.000000e-08
GCST002874_56	Psoriasis	9.000000e-07
GCST002874_64	Psoriasis	3.000000e-10
GCST003268_25	Psoriasis vulgaris	1.000000e-23
GCST003270_9	Psoriatic arthritis	1.000000e-17
GCST004131_98	Inflammatory bowel disease	4.000000e-10
GCST004133_60	Ulcerative colitis	6.000000e-10
GCST005527_11	Psoriasis	4.000000e-45
GCST005580_245	Intraocular pressure	7.000000e-16
GCST005580_32	Intraocular pressure	3.000000e-13
GCST007327_125	Smoking status (ever vs never smokers)	3.000000e-09
GCST009266_8	Dental caries (decayed and filled deciduous tooth surfaces)	2.000000e-06
GCST010002_332	Refractive error	3.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:1001494	psoriasis vulgaris
EFO:0004695	intraocular pressure measurement
EFO:0004318	smoking behavior

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002178	Candidiasis, Chronic Mucocutaneous	C01.150.703.160.088; C01.150.703.302.100; C01.800.200.100; C17.800.838.208.165; C23.550.291.500.250
D008179	Lupus Erythematosus, Discoid	C17.300.475.479; C17.800.480.479

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523586 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs76228616	Toxicity	3	nevirapine	HIV infectious disease

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs76228616	TRAF3IP2, TRAF3IP2-AS1	3	2.50	1	nevirapine
rs33980500	TRAF3IP2, TRAF3IP2-AS1		0.00	0
rs3777909	TRAF3IP2, TRAF3IP2-AS1		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, increases methylation	5
Cisplatin	affects expression, increases expression, affects cotreatment, decreases expression	3
sodium arsenite	decreases expression, increases abundance	2
Lipopolysaccharides	increases expression, affects response to substance	2
TL8-506	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, increases oxidation	1
pirinixic acid	affects binding, increases activity, increases expression	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
ciglitazone	increases expression, affects binding	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	increases expression	1
dorsomorphin	affects cotreatment, 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
Decitabine	affects expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	decreases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Hesperidin	decreases reaction, increases cleavage, increases expression, increases phosphorylation	1
Lead	decreases expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Piroxicam	affects cotreatment, decreases expression	1

Cellosaurus cell lines

6 cell lines: 3 transformed cell line, 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A8CK	HEK-Blue IL-17C	Transformed cell line	Female
CVCL_E4JD	Genomeditech HEK-293 H_IL17A Reporter	Transformed cell line	Female
CVCL_TT59	HAP1 TRAF3IP2 (-) 1	Cancer cell line	Male
CVCL_TT60	HAP1 TRAF3IP2 (-) 2	Cancer cell line	Male
CVCL_TT61	HAP1 TRAF3IP2 (-) 3	Cancer cell line	Male
CVCL_UF32	HEK-Blue IL-17	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00001680	PHASE2	COMPLETED	A Pilot Trial of Topical Thalidomide for the Management of Chronic Discoid Lupus Erythematosus
NCT00625157	PHASE2	COMPLETED	Efficacy and Safety of ASF-1096 Cream 0.5% in the Treatment of Discoid Lupus Erythematosus (DLE) Lesions (2)
NCT00625521	PHASE2	COMPLETED	Efficacy and Safety of ASF-1096 Cream 0.5% in the Treatment of Discoid Lupus Erythematosus (DLE) Lesions
NCT00797784	PHASE2	UNKNOWN	The Safety and Efficacy of Etanercept (Enbrel®) for the Treatment of Discoid Lupus Erythematosus
NCT03866317	PHASE2	WITHDRAWN	A Study to Assess the Safety and Efficacy of Secukinumab in Alleviating Symptoms of Discoid Lupus Erythematosus
NCT03958955	PHASE2	TERMINATED	Efficacy and Safety of Delgocitinib Cream in Discoid Lupus Erythematosus.
NCT04908280	PHASE2	COMPLETED	Study of Ruxolitinib Cream for the Treatment of Discoid Lupus Erythematosus
NCT05591222	PHASE2	TERMINATED	Study of Daxdilimab (HZN-7734) in Participants With Moderate-to-Severe Primary Discoid Lupus Erythematosus
NCT06261021	PHASE2	RECRUITING	Study to Evaluate the Efficacy of Ruxolitinib 1.5% Cream in Adult Subjects with Discoid Lupus Erythematosus
NCT07557927	PHASE2	NOT_YET_RECRUITING	A Multicentre, Randomised, Double-blind, Positive-control Clinical Trial Evaluating Dihydroartemisinin Tablets for the Treatment of Discoid Lupus Erythematosus
NCT01386437	Not specified	RECRUITING	Natural History of Individuals With Immune System Problems That Lead to Fungal Infections
NCT03736252	Not specified	COMPLETED	Effectiveness of a Neoprene CMC Joint Orthosis
NCT05896410	Not specified	UNKNOWN	3D-Printed Hand Orthosis Versus Thermoplastic Orthosis
NCT00708916	PHASE1/PHASE2	COMPLETED	Safety Study of Clinical and Immune Effects of Phosphodiesterase 4 (PDE-4) Inhibitor in Cutaneous Lupus Patients
NCT03159936	EARLY_PHASE1	TERMINATED	Oral Tofacitinib in Adult Subjects With Discoid Lupus Erythematosus (DLE) and Systemic Lupus Erythematosus (SLE)
NCT05362188	EARLY_PHASE1	COMPLETED	Topical Nicotinamide in Treatment of DLE
NCT00608673	Not specified	COMPLETED	Comparing the Therapeutic Efficacy of Pimecrolimus Cream With Betamethasone Cream for Discoid Lupus Erythematosus
NCT00691769	Not specified	COMPLETED	Expression of Fas Protein in Skin Biopsies of Participants With Scarring Alopecia
NCT02125695	Not specified	COMPLETED	Pilot Tape Harvesting Study