TRAFD1

Summary

TRAFD1 (TRAF-type zinc finger domain containing 1, HGNC:24808) is a protein-coding gene on chromosome 12q24.13, encoding TRAF-type zinc finger domain-containing protein 1 (O14545). Negative feedback regulator that controls excessive innate immune responses.

The innate immune system confers host defense against viral and microbial infection, and TRAFD1 is a negative feedback regulator that controls excessive immune responses (Sanada et al., 2008 [PubMed 18849341]).

Source: NCBI Gene 10906 — RefSeq curated summary.

At a glance

• GWAS associations: 21
• Clinical variants (ClinVar): 83 total
• Druggable target: yes
• MANE Select transcript: NM_006700

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24808
Approved symbol	TRAFD1
Name	TRAF-type zinc finger domain containing 1
Location	12q24.13
Locus type	gene with protein product
Status	Approved
Aliases	FLN29
Ensembl gene	ENSG00000135148
Ensembl biotype	protein_coding
OMIM	613197
Entrez	10906

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 26 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000257604, ENST00000412615, ENST00000547063, ENST00000548092, ENST00000548277, ENST00000549358, ENST00000550051, ENST00000552890, ENST00000552896, ENST00000880364, ENST00000880365, ENST00000880366, ENST00000880367, ENST00000880368, ENST00000880369, ENST00000880370, ENST00000880371, ENST00000880372, ENST00000917398, ENST00000917399, ENST00000917400, ENST00000917401, ENST00000964247, ENST00000964248, ENST00000964249, ENST00000964250, ENST00000964251, ENST00000964252, ENST00000964253, ENST00000964254

RefSeq mRNA: 2 — MANE Select: NM_006700 NM_001143906, NM_006700

CCDS: CCDS9160

Canonical transcript exons

ENST00000412615 — 12 exons

Exon	Start	End
ENSE00002209508	112152427	112152499
ENSE00002213941	112151801	112152140
ENSE00002288538	112149751	112149871
ENSE00002358944	112152735	112153604
ENSE00002361933	112125560	112125618
ENSE00003505143	112130511	112130569
ENSE00003559409	112148074	112148304
ENSE00003584404	112134738	112134873
ENSE00003598882	112135013	112135066
ENSE00003683204	112145586	112145662
ENSE00003686133	112140819	112141224
ENSE00003790604	112142089	112142295

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 98.80.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.6707 / max 647.5658, expressed in 1816 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
128064	27.3347	1813
128063	1.5989	1028
128062	0.8150	511
128065	0.4850	248
128067	0.3389	34
128066	0.0593	19
128068	0.0390	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	98.80	gold quality
oocyte	CL:0000023	98.21	gold quality
monocyte	CL:0000576	96.17	gold quality
mononuclear cell	CL:0000842	95.78	gold quality
leukocyte	CL:0000738	95.71	gold quality
granulocyte	CL:0000094	94.58	gold quality
calcaneal tendon	UBERON:0003701	93.49	gold quality
muscle layer of sigmoid colon	UBERON:0035805	92.88	gold quality
cortical plate	UBERON:0005343	92.56	gold quality
islet of Langerhans	UBERON:0000006	92.32	gold quality
skin of leg	UBERON:0001511	92.32	gold quality
blood	UBERON:0000178	92.13	gold quality
skin of abdomen	UBERON:0001416	92.11	gold quality
ganglionic eminence	UBERON:0004023	92.11	gold quality
esophagus mucosa	UBERON:0002469	91.36	gold quality
ventricular zone	UBERON:0003053	91.18	gold quality
right testis	UBERON:0004534	90.95	gold quality
stromal cell of endometrium	CL:0002255	90.82	gold quality
lymph node	UBERON:0000029	90.73	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	90.72	gold quality
left testis	UBERON:0004533	90.53	gold quality
esophagus	UBERON:0001043	90.45	gold quality
rectum	UBERON:0001052	90.35	gold quality
vermiform appendix	UBERON:0001154	90.35	gold quality
zone of skin	UBERON:0000014	89.98	gold quality
smooth muscle tissue	UBERON:0001135	89.95	gold quality
spleen	UBERON:0002106	89.83	gold quality
gall bladder	UBERON:0002110	89.76	gold quality
upper lobe of left lung	UBERON:0008952	89.76	gold quality
lower esophagus	UBERON:0013473	89.54	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7381	yes	886.45
E-MTAB-7037	yes	297.65
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

21 targeting TRAFD1, 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-4283	100.00	66.42	2097
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-646	99.68	67.84	1645
HSA-MIR-3660	99.68	67.33	1149
HSA-MIR-4526	99.68	67.07	1136
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-7159-3P	99.51	70.17	1920
HSA-MIR-4519	99.48	66.10	859
HSA-MIR-6830-5P	99.01	68.73	1884
HSA-MIR-6501-3P	98.71	67.45	1480
HSA-MIR-624-3P	98.37	67.06	1067
HSA-MIR-3187-3P	97.38	65.80	904
HSA-MIR-4670-3P	97.37	68.35	1378
HSA-MIR-6730-3P	97.03	67.54	889
HSA-MIR-4529-5P	96.74	65.77	569
HSA-MIR-3943	95.87	64.57	523
HSA-MIR-6796-5P	95.37	66.08	1120

Literature-anchored findings (GeneRIF, showing 3)

• FLN29 is a new negative feedback regulator of TLR signaling (PMID:16221674)
• FLN29, in addition to playing a negative regulatory role in the TLR4 signaling pathway, negatively regulates the RIG-I-like helicase signaling pathway at the level of IPS-1/TRAF6 and IPS-1/TRAF3 complexes (PMID:18849341)
• Integrative Multiomics and Regulatory Network Analyses Uncovers the Role of OAS3, TRAFD1, miR-222-3p, and miR-125b-5p in Hepatitis E Virus Infection. (PMID:36672782)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	trafd1	ENSDARG00000075123
mus_musculus	Trafd1	ENSMUSG00000042726
rattus_norvegicus	Trafd1	ENSRNOG00000001351

Paralogs (1): XAF1 (ENSG00000132530)

Protein

Protein identifiers

TRAF-type zinc finger domain-containing protein 1 — O14545 (reviewed: O14545)

Alternative names: Protein FLN29

All UniProt accessions (5): O14545, F8VNX8, F8VVF3, F8VWK2, S4R2Z9

UniProt curated annotations — full annotation on UniProt →

Function. Negative feedback regulator that controls excessive innate immune responses. Regulates both Toll-like receptor 4 (TLR4) and DDX58/RIG1-like helicases (RLH) pathways. May inhibit the LTR pathway by direct interaction with TRAF6 and attenuation of NF-kappa-B activation. May negatively regulate the RLH pathway downstream from MAVS and upstream of NF-kappa-B and IRF3.

Subunit / interactions. Interacts with MAVS, TICAM1, TRAF1, TRAF2, TRAF3. Interacts with TRAF6.

Isoforms (2)

UniProt ID	Names	Canonical?
O14545-1	1	yes
O14545-2	2

RefSeq proteins (2): NP_001137378, NP_006691* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR049439	TRAFD1-XIAF1_Znf	Domain
IPR051986	Innate_Immune_Apopt_Reg	Family

Pfam: PF21366

UniProt features (27 total): modified residue 10, strand 4, helix 3, splice variant 2, region of interest 2, compositionally biased region 2, initiator methionine 1, chain 1, sequence conflict 1, zinc finger region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2D9K	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14545-F1	58.45	0.03

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): 320, 326, 327, 409, 415, 430, 470, 2, 191, 278

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 268 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, CMYB_01, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_NEGATIVE_REGULATION_OF_INNATE_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_BIOTIC_STIMULUS, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_REGULATION_OF_IMMUNE_RESPONSE, RICKMAN_METASTASIS_DN, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_NEGATIVE_REGULATION_OF_DEFENSE_RESPONSE

GO Biological Process (1): negative regulation of innate immune response (GO:0045824)

GO Molecular Function (3): zinc ion binding (GO:0008270), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (1): mitochondrion (GO:0005739)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of response to biotic stimulus	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
innate immune response	1
regulation of innate immune response	1
negative regulation of immune response	1
transition metal ion binding	1
binding	1
cation binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1500 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRAFD1	TRAF6	Q9Y4K3	641
TRAFD1	MAVS	Q7Z434	614
TRAFD1	TICAM1	Q8IUC6	604
TRAFD1	NAA25	Q14CX7	595
TRAFD1	RIGI	O95786	570
TRAFD1	TMEM225	Q6GV28	543
TRAFD1	TRAF1	Q13077	524
TRAFD1	TMEM116	Q8NCL8	512
TRAFD1	TRAF3	Q13114	511
TRAFD1	TENT5A	Q96IP4	497
TRAFD1	IRF3	Q14653	491
TRAFD1	BORCS7	Q96B45	475
TRAFD1	DHRS12	A0PJE2	462
TRAFD1	NUDT17	P0C025	462
TRAFD1	TMCO5A	Q8N6Q1	461

IntAct

84 interactions, top by confidence:

A	B	Type	Score
NGLY1	TRAFD1	psi-mi:“MI:0915”(physical association)	0.780
TRAFD1	NGLY1	psi-mi:“MI:0915”(physical association)	0.780
CFTR	TRAFD1	psi-mi:“MI:0915”(physical association)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
TRAFD1	HTT	psi-mi:“MI:0915”(physical association)	0.550
HTT	TRAFD1	psi-mi:“MI:0915”(physical association)	0.550
XKRX	FAM234B	psi-mi:“MI:0914”(association)	0.530
TRAFD1	ACAD11	psi-mi:“MI:0914”(association)	0.530
KDELR1	TRAFD1	psi-mi:“MI:0914”(association)	0.530
ILK	ILVBL	psi-mi:“MI:0914”(association)	0.530
BBS4	TRAFD1	psi-mi:“MI:0914”(association)	0.510
TNFAIP3	LRRIQ3	psi-mi:“MI:0914”(association)	0.420
TRAF6	TRAFD1	psi-mi:“MI:0915”(physical association)	0.400
TRAFD1	Traf6	psi-mi:“MI:0915”(physical association)	0.400
TRAFD1	H1-4	psi-mi:“MI:0915”(physical association)	0.400
	TRAFD1	psi-mi:“MI:0915”(physical association)	0.370
TRAFD1	psaA	psi-mi:“MI:0915”(physical association)	0.370
OTUB1	EPM2A	psi-mi:“MI:0914”(association)	0.350

BioGRID (91): NGLY1 (Two-hybrid), TRAFD1 (Affinity Capture-MS), TRAFD1 (Affinity Capture-MS), TRAFD1 (Affinity Capture-MS), TRAFD1 (Affinity Capture-MS), TRAFD1 (Affinity Capture-MS), TRAFD1 (Affinity Capture-MS), TRAFD1 (Affinity Capture-MS), TRAFD1 (Affinity Capture-MS), NAA15 (Affinity Capture-MS), ACAD11 (Affinity Capture-MS), ASPM (Affinity Capture-MS), TRAFD1 (Affinity Capture-MS), BTBD1 (Affinity Capture-MS), TRAFD1 (Affinity Capture-MS)

ESM2 similar proteins: A2VE56, A6QPH9, I3LHS8, O08781, O14545, O54836, P0C6S7, Q14CM0, Q3SZY7, Q3U2E2, Q497H0, Q4R3D6, Q4R970, Q58D05, Q5F3F2, Q5FWF5, Q5R7S6, Q5RDJ2, Q5U2M7, Q5VT97, Q66J85, Q68FE8, Q69Z69, Q6DGF4, Q6FIF0, Q6N043, Q6P2K3, Q70EL2, Q7Z6G8, Q8BIZ1, Q8IWR0, Q8K214, Q8K387, Q8N7W2, Q8N9Z9, Q8NA31, Q8ND82, Q8QFX1, Q91YD3, Q96B23

Diamond homologs: O14545, Q3UDK1, Q4R970, Q58D05, Q5NBU8, Q6GPH4, Q99MM4, Q60803, Q58DH1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	61
Likely benign	8
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2344 predictions. Top by Δscore:

Variant	Effect	Δscore
12:112130453:T:G	acceptor_gain	1.0000
12:112134722:T:TA	acceptor_gain	1.0000
12:112134733:C:A	acceptor_gain	1.0000
12:112134736:A:AG	acceptor_gain	1.0000
12:112134737:G:GA	acceptor_gain	1.0000
12:112134737:GC:G	acceptor_gain	1.0000
12:112134737:GCA:G	acceptor_gain	1.0000
12:112134737:GCAA:G	acceptor_gain	1.0000
12:112140978:G:GT	donor_gain	1.0000
12:112142087:A:AG	acceptor_gain	1.0000
12:112142088:G:GA	acceptor_gain	1.0000
12:112142088:GTT:G	acceptor_gain	1.0000
12:112142236:GGGCC:G	donor_gain	1.0000
12:112142237:GGCCG:G	donor_gain	1.0000
12:112142270:TCCC:T	donor_gain	1.0000
12:112148073:GACAA:G	acceptor_gain	1.0000
12:112148306:T:A	donor_loss	1.0000
12:112149852:G:GT	donor_gain	1.0000
12:112149870:GG:G	donor_gain	1.0000
12:112149871:GG:G	donor_gain	1.0000
12:112152425:A:AG	acceptor_gain	1.0000
12:112152425:AGT:A	acceptor_gain	1.0000
12:112152426:G:GT	acceptor_gain	1.0000
12:112152426:GTG:G	acceptor_gain	1.0000
12:112152498:AGGT:A	donor_loss	1.0000
12:112152500:GTA:G	donor_loss	1.0000
12:112152501:T:G	donor_loss	1.0000
12:112125672:G:GT	donor_gain	0.9900
12:112125673:A:T	donor_gain	0.9900
12:112130452:A:AG	acceptor_gain	0.9900

AlphaMissense

3851 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:112140828:T:C	C83R	0.999
12:112148260:T:C	F372L	0.999
12:112148262:C:A	F372L	0.999
12:112148262:C:G	F372L	0.999
12:112140849:T:C	C90R	0.998
12:112149757:T:A	C389S	0.998
12:112149758:G:C	C389S	0.998
12:112130559:T:A	C13S	0.997
12:112130560:G:C	C13S	0.997
12:112134792:G:C	R34S	0.997
12:112134792:G:T	R34S	0.997
12:112134805:T:C	C39R	0.997
12:112135019:T:C	C64R	0.997
12:112135025:T:A	C66S	0.997
12:112135026:G:C	C66S	0.997
12:112140828:T:A	C83S	0.997
12:112140829:G:C	C83S	0.997
12:112140859:G:A	C93Y	0.997
12:112140906:T:A	C109S	0.997
12:112140906:T:C	C109R	0.997
12:112140907:G:A	C109Y	0.997
12:112140907:G:C	C109S	0.997
12:112148254:T:C	C370R	0.997
12:112148299:C:G	H385D	0.997
12:112149757:T:C	C389R	0.997
12:112130559:T:C	C13R	0.996
12:112134772:C:G	H28D	0.996
12:112134784:T:A	C32S	0.996
12:112134784:T:C	C32R	0.996
12:112134785:G:C	C32S	0.996

dbSNP variants (sampled 300 via entrez): RS1000014158 (12:112140015 AAAT>A,AAATAAT), RS1000021182 (12:112128845 A>G), RS1000029512 (12:112129804 A>G), RS1000068929 (12:112147765 A>G), RS1000128050 (12:112140362 A>G), RS1000169459 (12:112152310 G>T), RS1000177512 (12:112133225 G>C), RS1000288358 (12:112125353 T>C), RS1000356480 (12:112147517 A>G), RS1000589255 (12:112136575 G>C), RS1000692481 (12:112144596 C>G,T), RS1000695185 (12:112133001 A>G), RS1000736847 (12:112153145 G>A,C), RS1001020812 (12:112138457 G>A), RS1001133469 (12:112138661 C>T)

Disease associations

OMIM: gene MIM:613197 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

21 associations (top):

Study	Trait	p-value
GCST000043_1	Type 1 diabetes	2.000000e-14
GCST000499_7	Hemoglobin	1.000000e-11
GCST002783_300	Body mass index	5.000000e-07
GCST002783_556	Body mass index	6.000000e-07
GCST003129_17	Primary biliary cholangitis	3.000000e-08
GCST005329_1	Coffee consumption	2.000000e-16
GCST005439_1	Response to alcohol consumption (flushing response)	2.000000e-14
GCST005440_17	Alcohol dependence symptom count	6.000000e-10
GCST005441_8	Alcohol consumption (max-drinks)	2.000000e-12
GCST005752_113	Systemic lupus erythematosus	3.000000e-07
GCST005951_75	Body mass index	2.000000e-11
GCST007439_2	Aspartate aminotransferase levels	3.000000e-13
GCST007440_2	Alanine aminotransferase levels	2.000000e-08
GCST010083_81	Hemoglobin levels	1.000000e-10
GCST012177_3	Confectionary intake	3.000000e-29
GCST90002398_150	Neutrophil count	2.000000e-11
GCST90002400_730	Plateletcrit	5.000000e-55
GCST90002402_152	Platelet count	4.000000e-52
GCST90002407_295	White blood cell count	1.000000e-14
GCST90016667_14	Spleen volume	2.000000e-58
GCST90016667_6	Spleen volume	1.000000e-59

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004509	hemoglobin measurement
EFO:0004340	body mass index
EFO:0006782	cups of coffee per day measurement
EFO:0007835	alcohol dependence measurement
EFO:0004736	aspartate aminotransferase measurement
EFO:0003939	energy intake
EFO:0004833	neutrophil count
EFO:0007985	platelet crit
EFO:0004309	platelet count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066259 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cadmium Chloride	decreases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
sulforaphane	decreases expression	1
sodium arsenite	affects cotreatment, increases abundance, increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
cupric chloride	decreases expression	1
coumarin	decreases phosphorylation	1
adefovir dipivoxil	decreases expression	1
abrine	increases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	decreases expression	1
Bortezomib	increases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Cidofovir	increases expression	1
Acetaminophen	decreases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Caffeine	affects phosphorylation	1
Cisplatin	increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Clodronic Acid	affects expression	1
Diethylstilbestrol	decreases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Estradiol	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Ifosfamide	increases expression	1
Ivermectin	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652694	Binding	Binding affinity to human TRAFD1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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