TIRAP

Summary

TIRAP (TIR domain containing adaptor protein, HGNC:17192) is a protein-coding gene on chromosome 11q24.2, encoding Toll/interleukin-1 receptor domain-containing adapter protein (P58753). Adapter involved in TLR2, TLR4 and RAGE signaling pathways in the innate immune response.

The innate immune system recognizes microbial pathogens through Toll-like receptors (TLRs), which identify pathogen-associated molecular patterns. Different TLRs recognize different pathogen-associated molecular patterns and all TLRs have a Toll-interleukin 1 receptor (TIR) domain, which is responsible for signal transduction. The protein encoded by this gene is a TIR adaptor protein involved in the TLR4 signaling pathway of the immune system. It activates NF-kappa-B, MAPK1, MAPK3 and JNK, which then results in cytokine secretion and the inflammatory response. Alternative splicing of this gene results in several transcript variants; however, not all variants have been fully described.

Source: NCBI Gene 114609 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 35 total
• MANE Select transcript: NM_001318777

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17192
Approved symbol	TIRAP
Name	TIR domain containing adaptor protein
Location	11q24.2
Locus type	gene with protein product
Status	Approved
Aliases	Mal, wyatt
Ensembl gene	ENSG00000150455
Ensembl biotype	protein_coding
OMIM	606252
Entrez	114609

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 20 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000392678, ENST00000392679, ENST00000392680, ENST00000462401, ENST00000467006, ENST00000479770, ENST00000488598, ENST00000700488, ENST00000700489, ENST00000700490, ENST00000700491, ENST00000700492, ENST00000700493, ENST00000700494, ENST00000700495, ENST00000700496, ENST00000871298, ENST00000871299, ENST00000871300, ENST00000871301, ENST00000871302, ENST00000871303, ENST00000937665, ENST00000952352, ENST00000952353, ENST00000952354

RefSeq mRNA: 4 — MANE Select: NM_001318777 NM_001039661, NM_001318776, NM_001318777, NM_148910

CCDS: CCDS41731, CCDS8472

Canonical transcript exons

ENST00000392679 — 5 exons

Exon	Start	End
ENSE00000994997	126292477	126293055
ENSE00001281848	126290462	126290585
ENSE00001512742	126283093	126283153
ENSE00003663369	126290803	126290961
ENSE00003979960	126293668	126294933

Expression profiles

Bgee: expression breadth ubiquitous, 171 present calls, max score 84.63.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.1434 / max 38.9323, expressed in 1769 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
117494	6.6824	1754
117495	0.8518	562
117493	0.3861	185
117496	0.2231	89

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oviduct epithelium	UBERON:0004804	84.63	gold quality
buccal mucosa cell	CL:0002336	84.47	gold quality
monocyte	CL:0000576	83.30	gold quality
leukocyte	CL:0000738	83.13	gold quality
bone marrow cell	CL:0002092	82.46	gold quality
islet of Langerhans	UBERON:0000006	79.67	gold quality
rectum	UBERON:0001052	79.07	gold quality
smooth muscle tissue	UBERON:0001135	78.39	gold quality
left ovary	UBERON:0002119	78.27	gold quality
right ovary	UBERON:0002118	78.17	gold quality
right lobe of liver	UBERON:0001114	78.09	gold quality
minor salivary gland	UBERON:0001830	77.87	gold quality
stromal cell of endometrium	CL:0002255	77.77	gold quality
fallopian tube	UBERON:0003889	77.67	gold quality
gall bladder	UBERON:0002110	77.64	gold quality
vermiform appendix	UBERON:0001154	77.54	gold quality
body of pancreas	UBERON:0001150	77.38	gold quality
granulocyte	CL:0000094	77.16	gold quality
ovary	UBERON:0000992	77.08	gold quality
pancreas	UBERON:0001264	77.04	gold quality
right coronary artery	UBERON:0001625	76.98	gold quality
left adrenal gland	UBERON:0001234	76.93	gold quality
adrenal tissue	UBERON:0018303	76.84	gold quality
right adrenal gland	UBERON:0001233	76.77	gold quality
colonic epithelium	UBERON:0000397	76.71	gold quality
apex of heart	UBERON:0002098	76.71	gold quality
right adrenal gland cortex	UBERON:0035827	76.67	gold quality
transverse colon	UBERON:0001157	76.59	gold quality
small intestine Peyer’s patch	UBERON:0003454	76.28	gold quality
lower esophagus	UBERON:0013473	76.28	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-MTAB-6142	no	25.37
E-ANND-3	no	3.97

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 40)

• a role for TIRAP in mediating LPS-induced NF-kappaB activation and apoptosis in human endothelial cells (PMID:12083783)
• These results indicate the existence of another signal essential for I kappa B-zeta induction, which is specifically mediated by the Toll/interleukin-1 receptor (TIR) domain-mediated signaling pathway. (PMID:12565889)
• MyD88 and Mal/TIRAP are essential for LPS-induced I kappa B alpha phosphorylation, NF-kappa B activation, and interleukin 6 (IL-6) or IL-8 production in fibroblasts and endothelial cells in a pathway that also requires IKK2. (PMID:14630816)
• involvement of a previously uncharacterized, evolutionarily conserved TIR domain protein in innate immunity that is functionally distinct from other known TIR domain signaling adapters (PMID:15123841)
• activation of Rac1 leads to HIV-LTR trans-activation, mediated through TIRAP. Rac1 and TIRAP are important in TLR4 activation of HIV replication (PMID:15187145)
• role for Mal in TLR-mediated signaling in regulating NF-kappaB-dependent gene transcription via its interaction with TRAF6 (PMID:15247281)
• Mal phosphorylation has an effect on tyrosine during signaling by TLR2 and TLR4 and Btk is the kinase involved (PMID:16439361)
• TIRAP contains a PIP2 binding domain, which mediates TIRAP recruitment to the plasma membrane. TIRAP then functions to facilitate MyD88 delivery to activated TLR4 to initiate signal transduction. (PMID:16751103)
• These results suggest that PKCdelta binding to TIRAP/Mal promotes TLR signaling events. (PMID:17161867)
• Mal S180L variant attenuated TLR2 signal transduction and confers a protective effect against infectious diseases. (PMID:17322885)
• analysis offers additional evidence that the TLR4 pathway - in this case, TLR4 and its signaling molecule TIRAP - plays a role in susceptibility to inflammatory bowel diseases (PMID:17538633)
• A polymorphism modulating innate immunity signal transduction has recently been shown to influence human susceptibility to many different infections. (PMID:17610834)
• tyrosine phosphorylation of Mal is required for adapter signaling, regulates Mal interactions with TLR4 and receptor signaling, and is inhibited in endotoxin tolerance (PMID:18070880)
• The Mal S180L and TLR4 G299D polymorphisms do not contribute to RA susceptibility or severity either individually or in combination. (PMID:18180278)
• In fibroblast-like synoviocytes of rheumatoid arthritis patients, T-cell maturation-associated protein MAL is implicated in the cross-talk between focal adhesion kinase (FAK) and myeloid differentiation factor 88 (MyD88) pathways. (PMID:18292575)
• Analysis of association of the TIRAP (MAL) S180L variant and tuberculosis in three populations. (PMID:18305471)
• the TIRAP Leu180 allele was found to be a protective factor against developing tuberculosis and systemic lupus erythematosus (PMID:18417424)
• single nucleotide polymorphism, C558T, influences susceptibility to both meningeal and pulmonary tuberculosis (PMID:19120490)
• Similar frequencies of TLR2, TLR4, TLR9, and MAL genetic polymorphisms in populations with different histories of malaria exposure suggest that these innate immune pathways have not been under strong selective pressure by malaria. (PMID:19317913)
• Chagas disease patients who are heterozygous for the TIRAP S180L variant that leads to a decrease in signal transduction upon ligation of TLR2 or TLR4 to their respective ligand may have a lower risk of developing chronic Chagas cardiomyopathy. (PMID:19456234)
• A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP results in loss of MyD88 binding and reduced TLR2/TLR4 signaling. (PMID:19509286)
• individuals bearing the TIRAP 180L allele display an increased, innate immune response to TLR4 and TLR2 ligands, but not to TLR9 stimulation. (PMID:19509334)
• Mal specifically connects TLR2/6 to PI3K activation, PIP(3) generation and macrophage polarization. (PMID:19574958)
• the novel role for Mal in facilitating the direct recruitment of TRAF6 to the plasma membrane, which is necessary for TLR2- and TLR4-induced transactivation of NF-kappaB and regulation of the subsequent pro-inflammatory response. (PMID:19592497)
• A broad protective effect of TIRAP S180L against infectious diseases per se is not discernible (PMID:19602285)
• Polymorphisms in TIRAP do not appear to be involved in childhood tuberculosis susceptibility in South Africa, but may play a role in determining occurrence of tubercular meningitis (PMID:19693265)
• Data show that AIP1 is a novel GTPase-activating protein for Arf6, a small GTPase regulating cellular PIP(2) production and formation of the TLR4-TIRAP-MyD88 complex. (PMID:19948740)
• An Asp96Asn single nucleotide polymorphism prevents Mal from recruiting its signaling partner MyD88 to the plasma membrane and fails to induce NF-kappa B signaling in human tumor line Huh-7 hepatocytes. (PMID:20164415)
• Patients simultaneously carrying polymorphisms in TIRAP/Mal and TLR4 and patients homozygous for the TIRAP/Mal SNP had a significantly higher risk of severe infections after surgery (PMID:20525286)
• The recessive homozygous genotype for a single-nucleotide polymorphisms in the TIRAP (also known as MAL) gene (rs1893352) was strongly associated with nonmeningitis cases of haemophilus influenzae serotype b vaccine failure. (PMID:20804371)
• TIRAP gene might be associated with susceptibility to sepsis-associated acute lung injury in the Han Chinese population. (PMID:21118491)
• TIRAP G286A (D96N) polymorphism is associated with susceptibility to tuberculosis. (PMID:21218381)
• RA synovium showed abundant expression of TLR. RA synovitis tissue seems to be responsive to TLR ligands. (PMID:21324962)
• Data demonstrate a key role for Mal in mediating TLR2 and TLR4 activation of CREB and induction of CREB-responsive genes including Il-10. (PMID:21398611)
• Genetic variations in MyD88 adaptor-like are associated with atopic dermatitis (PMID:21399862)
• TIRAP S180L polymorphism is unlikely to substantially contribute to tuberculosis susceptibility (Meta-analysis) (PMID:21419702)
• Comparison of the tirap S180L genotypes between patients with mild malaria and those healthy individuals showed that the frequency of heterozygosity was significantly higher in infected than non-infected individuals. (PMID:21457584)
• TIRAP 180Leu was significantly associated with Behcet’s disease in UK, but not Middle Eastern, patients. (PMID:21705416)
• Blocking of the function of TIRAP and MyD88 largely abrogated intracellular signaling from ligand-activated RAGE (PMID:21829704)
• a molecular and structural basis for the role of MAL in TLR signaling and disease protection. (PMID:21873236)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tirap	ENSDARG00000074371
mus_musculus	Tirap	ENSMUSG00000032041
rattus_norvegicus	Tirap	ENSRNOG00000021420

Protein

Protein identifiers

Toll/interleukin-1 receptor domain-containing adapter protein — P58753 (reviewed: P58753)

Alternative names: Adaptor protein Wyatt, MyD88 adapter-like protein

All UniProt accessions (3): P58753, A0A8V8TPR1, F5H2K1

UniProt curated annotations — full annotation on UniProt →

Function. Adapter involved in TLR2, TLR4 and RAGE signaling pathways in the innate immune response. Acts via IRAK2 and TRAF-6, leading to the activation of NF-kappa-B, MAPK1, MAPK3 and JNK, and resulting in cytokine secretion and the inflammatory response. Positively regulates the production of TNF (TNF) and interleukin-6 (IL6).

Subunit / interactions. Homodimer. Also forms heterodimers with MYD88. May interact with PIK3AP1. Interacts with TLR4 and IRAK2 via their respective TIR domains. Interacts with BMX and TBK1. Interacts with EIF2AK2. Does not interact with IRAK1, nor TLR9. Interacts with TLR2. Interacts with RAGE/AGER. (Microbial infection) In case of infection, interacts with B.melitensis protein TcpB (AC Q8YF53); TcpB abolishes the TLR4-TIRAP interaction and downstream signaling.

Subcellular location. Cytoplasm. Cell membrane. Membrane.

Tissue specificity. Highly expressed in liver, kidney, spleen, skeletal muscle and heart. Also detected in peripheral blood leukocytes, lung, placenta, small intestine, thymus, colon and brain.

Post-translational modifications. Phosphorylated by IRAK1 and IRAK4. Also phosphorylated by BTK. Polyubiquitinated. Polyubiquitination follows phosphorylation by BTK and leads to TIRAP degradation.

Domain organisation. (Microbial infection) The TIR domain is structurally mimicked by the TIR domain of B.melitensis protein TcpB.

Polymorphism. Genetic variations in TIRAP have been proposed to influence susceptibility or resistance to invasive pneumococcal disease, malaria [MIM:611162], and tuberculosis [MIM:607948]. It may define the bacteremia susceptibility locus 1 (BACTS1) [MIM:614382]. Indeed it has been reported that heterozygous carriage of p.Ser180Leu in populations from the U.K., Vietnam, and several African countries may confer protection against invasive pneumococcal disease, bacteremia, malaria, and tuberculosis. However, analyzes of Russian, Ghanaian and Indonesian populations fail to replicate the association between p.Ser180Leu and susceptibility to tuberculosis formerly observed in West African and Algerian populations.

Isoforms (3)

UniProt ID	Names	Canonical?
P58753-1	1	yes
P58753-2	2
P58753-3	3

RefSeq proteins (4): NP_001034750, NP_001305705, NP_001305706, NP_683708 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000157	TIR_dom	Domain
IPR017279	Tol-interleuk_rcpt_adapt_Tirap	Family
IPR035897	Toll_tir_struct_dom_sf	Homologous_superfamily

Pfam: PF13676

UniProt features (30 total): helix 10, sequence variant 6, strand 4, disulfide bond 2, splice variant 2, chain 1, domain 1, mutagenesis site 1, turn 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
3UB2	X-RAY DIFFRACTION	2.4
4LQD	X-RAY DIFFRACTION	2.45
3UB3	X-RAY DIFFRACTION	2.75
2Y92	X-RAY DIFFRACTION	3.01
3UB4	X-RAY DIFFRACTION	3.1
9FQM	ELECTRON MICROSCOPY	3.3
4FZ5	X-RAY DIFFRACTION	3.6
5UZB	ELECTRON MICROSCOPY	7
2NDH	SOLUTION NMR
5T7Q	SOLUTION NMR
8JZM	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P58753-F1	74.87	0.53

Functional residue map

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

Disulfide bonds (2): 89–134, 142–174

Mutagenesis-validated functional residues (1):

Position	Phenotype
125	abolishes nf-kappa-b activation.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1236974	ER-Phagosome pathway
R-HSA-166058	MyD88:MAL(TIRAP) cascade initiated on plasma membrane
R-HSA-5602498	MyD88 deficiency (TLR2/4)
R-HSA-5603041	IRAK4 deficiency (TLR2/4)

MSigDB gene sets: 590 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_APICAL_PROTEIN_LOCALIZATION, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, REACTOME_INNATE_IMMUNE_SYSTEM, BENPORATH_ES_WITH_H3K27ME3, GOBP_MYELOID_LEUKOCYTE_MIGRATION, MODULE_169, GOBP_CELL_CHEMOTAXIS, BIOCARTA_MAL_PATHWAY, LU_IL4_SIGNALING, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_INFLAMMATORY_RESPONSE, GOBP_POSITIVE_REGULATION_OF_INTERLEUKIN_8_PRODUCTION

GO Biological Process (33): MyD88-dependent toll-like receptor signaling pathway (GO:0002755), inflammatory response (GO:0006954), cell surface receptor signaling pathway (GO:0007166), myeloid cell differentiation (GO:0030099), positive regulation of B cell proliferation (GO:0030890), positive regulation of protein-containing complex assembly (GO:0031334), response to lipopolysaccharide (GO:0032496), regulation of interferon-beta production (GO:0032648), positive regulation of interleukin-12 production (GO:0032735), positive regulation of interleukin-15 production (GO:0032738), positive regulation of interleukin-6 production (GO:0032755), positive regulation of interleukin-8 production (GO:0032757), positive regulation of tumor necrosis factor production (GO:0032760), positive regulation of toll-like receptor 2 signaling pathway (GO:0034137), positive regulation of toll-like receptor 3 signaling pathway (GO:0034141), toll-like receptor 4 signaling pathway (GO:0034142), positive regulation of toll-like receptor 4 signaling pathway (GO:0034145), TIRAP-dependent toll-like receptor 4 signaling pathway (GO:0035665), toll-like receptor TLR1:TLR2 signaling pathway (GO:0038123), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), innate immune response (GO:0045087), regulation of innate immune response (GO:0045088), positive regulation of JNK cascade (GO:0046330), defense response to Gram-positive bacterium (GO:0050830), positive regulation of ERK1 and ERK2 cascade (GO:0070374), 3’-UTR-mediated mRNA stabilization (GO:0070935), cellular response to bacterial lipopeptide (GO:0071221), cellular response to lipoteichoic acid (GO:0071223), positive regulation of neutrophil chemotaxis (GO:0090023), positive regulation of chemokine (C-X-C motif) ligand 1 production (GO:2000340), positive regulation of chemokine (C-X-C motif) ligand 2 production (GO:2000343), immune system process (GO:0002376), signal transduction (GO:0007165)

GO Molecular Function (9): protein kinase C binding (GO:0005080), phosphatidylinositol-4,5-bisphosphate binding (GO:0005546), protein-macromolecule adaptor activity (GO:0030674), signaling adaptor activity (GO:0035591), Toll-like receptor 4 binding (GO:0035662), Toll-like receptor 2 binding (GO:0035663), identical protein binding (GO:0042802), molecular adaptor activity (GO:0060090), protein binding (GO:0005515)

GO Cellular Component (8): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), cell surface (GO:0009986), endocytic vesicle (GO:0030139), extrinsic component of cytoplasmic side of plasma membrane (GO:0031234), ruffle membrane (GO:0032587), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Diseases associated with the TLR signaling cascade	2
Antigen processing-Cross presentation	1
Toll Like Receptor 4 (TLR4) Cascade	1
Toll Like Receptor TLR1:TLR2 Cascade	1
Toll Like Receptor TLR6:TLR2 Cascade	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of cytokine production	4
cellular anatomical structure	4
positive regulation of pattern recognition receptor signaling pathway	3
toll-like receptor signaling pathway	2
positive regulation of intracellular signal transduction	2
toll-like receptor 4 signaling pathway	2
protein binding	2
Toll-like receptor binding	2
binding	2
defense response	1
signal transduction	1
hemopoiesis	1
cell differentiation	1
regulation of B cell proliferation	1
B cell proliferation	1
positive regulation of lymphocyte proliferation	1
positive regulation of B cell activation	1
regulation of protein-containing complex assembly	1
positive regulation of cellular component biogenesis	1
positive regulation of cellular component organization	1
protein-containing complex assembly	1
response to molecule of bacterial origin	1
response to lipid	1
response to oxygen-containing compound	1
regulation of type I interferon production	1
interferon-beta production	1
interleukin-12 production	1
regulation of interleukin-12 production	1
interleukin-15 production	1
regulation of interleukin-15 production	1
interleukin-6 production	1
regulation of interleukin-6 production	1
interleukin-8 production	1
regulation of interleukin-8 production	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
positive regulation of tumor necrosis factor superfamily cytokine production	1
toll-like receptor 2 signaling pathway	1
regulation of toll-like receptor 2 signaling pathway	1
toll-like receptor 3 signaling pathway	1

Protein interactions and networks

STRING

1170 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TIRAP	TLR4	O00206	999
TIRAP	TLR2	O60603	998
TIRAP	IRAK1	P51617	997
TIRAP	TRAF6	Q9Y4K3	995
TIRAP	TLR1	Q15399	992
TIRAP	MYD88	P78397	992
TIRAP	TLR3	O15455	980
TIRAP	TLR6	Q9Y2C9	976
TIRAP	TLR5	O60602	935
TIRAP	TICAM2	Q86XR7	923
TIRAP	TICAM1	Q8IUC6	907
TIRAP	IRAK2	O43187	904
TIRAP	IRAK4	Q9NWZ3	897
TIRAP	SARM1	Q6SZW1	895
TIRAP	TLR9	Q9NR96	883

IntAct

73 interactions, top by confidence:

A	B	Type	Score
TIRAP	MYD88	psi-mi:“MI:0915”(physical association)	0.900
MYD88	TIRAP	psi-mi:“MI:0915”(physical association)	0.900
TLR4	TIRAP	psi-mi:“MI:0915”(physical association)	0.810
TLR4	TIRAP	psi-mi:“MI:0914”(association)	0.810
TIRAP	TLR4	psi-mi:“MI:0914”(association)	0.810
TIRAP	TIRAP	psi-mi:“MI:0915”(physical association)	0.700
TIRAP	TIRAP	psi-mi:“MI:0407”(direct interaction)	0.700
TIRAP	IRAK1	psi-mi:“MI:0914”(association)	0.620
TIRAP	IRAK1	psi-mi:“MI:0915”(physical association)	0.620
AGER	TIRAP	psi-mi:“MI:0914”(association)	0.560
AGER	TIRAP	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (91): CAMK2D (Affinity Capture-MS), CAMK2G (Affinity Capture-MS), DHPS (Affinity Capture-MS), NTMT1 (Affinity Capture-MS), BTBD9 (Affinity Capture-MS), KLHL24 (Affinity Capture-MS), TEP1 (Affinity Capture-MS), NTMT1 (Affinity Capture-MS), DHPS (Affinity Capture-MS), TEP1 (Affinity Capture-MS), CAMK2G (Affinity Capture-MS), CAMK2D (Affinity Capture-MS), TIRAP (Affinity Capture-Western), TIRAP (Reconstituted Complex), TIRAP (Affinity Capture-Western)

ESM2 similar proteins: A0A0G2JXN2, A1L134, A2RRU4, A4D2P6, A6QM06, O08773, O19131, O43566, O88842, O94827, P19438, P29590, P50555, P50747, P52734, P58753, P70295, P97260, P97492, P98174, Q0GA42, Q12770, Q16512, Q3TAA7, Q5MNU5, Q5R5T1, Q66T02, Q69Z89, Q6AZ51, Q6GQT6, Q6RFZ7, Q6SZW1, Q7TNM2, Q7Z4K8, Q8BH06, Q8BUM9, Q8C190, Q8N1F8, Q8N531, Q8NFR9

Diamond homologs: P0DUE1, P58753, Q99JY1

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
TIRAP	“up-regulates activity”	MYD88	binding
TLR4	up-regulates	TIRAP	binding
TLRs	“up-regulates activity”	TIRAP	binding
TLR4	“up-regulates activity”	TIRAP	binding
RNF216	“down-regulates quantity by destabilization”	TIRAP	ubiquitination
TIRAP	“up-regulates activity”	AGER	binding
CLIP1	“down-regulates activity”	TIRAP	binding
TIRAP	“up-regulates activity”	TRAF6	binding
TLR2	“up-regulates activity”	TIRAP	binding
TLR9	“up-regulates activity”	TIRAP	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 28 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
Interleukin-1 family signaling	6	85.9×	5e-09
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	6	60.1×	2e-08
MyD88 dependent cascade initiated on endosome	6	60.1×	2e-08
MyD88-independent TLR4 cascade	6	58.2×	2e-08
Toll Like Receptor 7/8 (TLR7/8) Cascade	6	58.2×	2e-08
Toll Like Receptor 10 (TLR10) Cascade	5	56.7×	4e-07
Toll Like Receptor 5 (TLR5) Cascade	5	56.7×	4e-07
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	7	56.1×	5e-09

GO biological processes:

GO term	Partners	Fold	FDR
MyD88-dependent toll-like receptor signaling pathway	5	222.9×	3e-09
toll-like receptor 4 signaling pathway	6	150.5×	5e-10
lipopolysaccharide-mediated signaling pathway	5	125.4×	3e-08
positive regulation of chemokine production	5	89.2×	1e-07
positive regulation of smooth muscle cell proliferation	5	78.7×	2e-07
positive regulation of interleukin-1 beta production	5	61.7×	5e-07
obsolete positive regulation of NF-kappaB transcription factor activity	5	48.9×	1e-06
positive regulation of tumor necrosis factor production	6	43.8×	2e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	17
Likely benign	6
Benign	10

Top pathogenic / likely-pathogenic (0)

SpliceAI

1004 predictions. Top by Δscore:

Variant	Effect	Δscore
11:126291504:T:G	donor_gain	1.0000
11:126292475:A:AG	acceptor_gain	1.0000
11:126292475:A:C	acceptor_loss	1.0000
11:126292475:AGACT:A	acceptor_gain	1.0000
11:126292476:G:GG	acceptor_gain	1.0000
11:126292476:GA:G	acceptor_gain	1.0000
11:126292476:GACT:G	acceptor_gain	1.0000
11:126292476:GACTG:G	acceptor_gain	1.0000
11:126293051:GCGTT:G	donor_gain	1.0000
11:126293053:GTT:G	donor_gain	1.0000
11:126293056:G:GG	donor_gain	1.0000
11:126283153:GGTGA:G	donor_loss	0.9900
11:126283154:GTG:G	donor_loss	0.9900
11:126283155:T:G	donor_loss	0.9900
11:126291566:GAGT:G	donor_gain	0.9900
11:126291568:GT:G	donor_gain	0.9900
11:126292476:GAC:G	acceptor_gain	0.9900
11:126293040:G:GT	donor_gain	0.9900
11:126293061:C:G	donor_gain	0.9900
11:126293073:G:GT	donor_gain	0.9900
11:126293095:C:G	donor_gain	0.9900
11:126283150:GCAG:G	donor_gain	0.9800
11:126283154:G:GG	donor_gain	0.9800
11:126289835:C:T	donor_gain	0.9800
11:126291354:G:T	donor_gain	0.9800
11:126292474:CAGA:C	acceptor_gain	0.9800
11:126293070:G:GT	donor_gain	0.9800
11:126290586:G:GG	donor_gain	0.9700
11:126291354:G:GT	donor_gain	0.9700
11:126292471:CCACA:C	acceptor_gain	0.9700

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000316851 (11:126288156 A>C), RS1000339157 (11:126294684 A>G), RS1000448835 (11:126283139 T>A,C), RS1000475176 (11:126294286 T>A,C), RS1000607267 (11:126289439 A>T), RS1000863931 (11:126283105 GAGCCCGCGC>G), RS1000959452 (11:126289955 C>A,T), RS1000988569 (11:126283249 G>A), RS1001041071 (11:126283023 G>A), RS1001195267 (11:126290210 G>A,T), RS1001553954 (11:126291348 G>T), RS1001599391 (11:126291047 C>G), RS1001857314 (11:126284469 C>A), RS1002285492 (11:126291059 A>G), RS1002452017 (11:126285809 G>A,T)

Disease associations

OMIM: gene MIM:606252 | disease phenotypes: MIM:614382, MIM:611162

GenCC curated gene-disease

Mondo (3): bacteremia, susceptibility (MONDO:0000108), bacteremia, susceptibility to, 1 (MONDO:0013723), malaria, susceptibility to (MONDO:0021024)

Orphanet (1): Malaria (Orphanet:673)

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST004617_140	Eosinophil percentage of granulocytes	1.000000e-10
GCST004623_55	Neutrophil percentage of granulocytes	3.000000e-12
GCST006585_1390	Blood protein levels	9.000000e-16
GCST009731_14	Blood protein levels in cardiovascular risk	2.000000e-12

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007996	eosinophil percentage of granulocytes
EFO:0007994	neutrophil percentage of granulocytes
EFO:0008137	galectin-3 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs8177374	Efficacy	3	ustekinumab	Psoriasis

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs8177374	TIRAP	3	3.00	1	ustekinumab

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
dicrotophos	increases expression	1
kojic acid	decreases expression	1
beta-lapachone	increases expression	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	increases methylation	1
ferrous chloride	decreases expression	1
ceric oxide	decreases expression	1
pentanal	decreases expression	1
cobalt oxide	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
lipopolysaccharide, E coli O55-B5	decreases reaction, increases expression	1
9,10-dihydro-2,5-dimethoxyphenanthrene-1,7-diol	increases expression, decreases reaction	1
Sunitinib	decreases expression	1
Allergens	increases expression	1
Antigens, Viral	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Chelating Agents	increases expression, affects binding	1
Copper	affects binding, increases expression	1
Demecolcine	decreases expression	1
Dimethyl Sulfoxide	affects expression	1
Formaldehyde	decreases expression	1
Methapyrilene	increases methylation	1
Phthalic Acids	increases methylation	1
Valproic Acid	decreases expression	1
Vincristine	decreases expression	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	decreases expression	1
Acrylamide	increases expression	1

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D8CH	Ubigene A-549 TIRAP KO	Cancer cell line	Male
CVCL_D8X5	Ubigene HCT 116 TIRAP KO	Cancer cell line	Male
CVCL_D9UA	Ubigene HEK293 TIRAP KO	Transformed cell line	Female
CVCL_E0R1	Ubigene HeLa TIRAP KO	Cancer cell line	Female
CVCL_TS43	HAP1 TIRAP (-) 1	Cancer cell line	Male
CVCL_TS44	HAP1 TIRAP (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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