TLR3

Summary

TLR3 (toll like receptor 3, HGNC:11849) is a protein-coding gene on chromosome 4q35.1, encoding Toll-like receptor 3 (O15455). Key component of innate and adaptive immunity.

The protein encoded by this gene is a member of the Toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This receptor is most abundantly expressed in placenta and pancreas, and is restricted to the dendritic subpopulation of the leukocytes. It recognizes dsRNA associated with viral infection, and induces the activation of NF-kappaB and the production of type I interferons. It thus plays a role in host defense against multiple viruses.

Source: NCBI Gene 7098 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency 83, susceptibility to viral infections (Strong, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 593 total
• Phenotypes (HPO): 42
• Druggable target: yes
• MANE Select transcript: NM_003265

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11849
Approved symbol	TLR3
Name	toll like receptor 3
Location	4q35.1
Locus type	gene with protein product
Status	Approved
Aliases	CD283
Ensembl gene	ENSG00000164342
Ensembl biotype	protein_coding
OMIM	603029
Entrez	7098

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 9 protein_coding, 1 non_stop_decay, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000296795, ENST00000504367, ENST00000508051, ENST00000512264, ENST00000513189, ENST00000698351, ENST00000698352, ENST00000698353, ENST00000698354, ENST00000949725, ENST00000949726, ENST00000949727

RefSeq mRNA: 1 — MANE Select: NM_003265 NM_003265

CCDS: CCDS3846

Canonical transcript exons

ENST00000296795 — 5 exons

Exon	Start	End
ENSE00001375046	186084645	186088073
ENSE00002039207	186069156	186069248
ENSE00003647762	186082320	186084172
ENSE00003973384	186078840	186079031
ENSE00003973388	186076613	186077060

Expression profiles

Bgee: expression breadth ubiquitous, 232 present calls, max score 92.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.2912 / max 144.9735, expressed in 1048 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
50892	4.2912	1048

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	92.84	gold quality
palpebral conjunctiva	UBERON:0001812	87.77	gold quality
placenta	UBERON:0001987	87.57	gold quality
rectum	UBERON:0001052	84.33	gold quality
sperm	CL:0000019	83.91	silver quality
duodenum	UBERON:0002114	83.65	gold quality
gall bladder	UBERON:0002110	83.57	gold quality
esophagus squamous epithelium	UBERON:0006920	81.68	gold quality
calcaneal tendon	UBERON:0003701	81.26	gold quality
colonic epithelium	UBERON:0000397	81.21	gold quality
male germ cell	CL:0000015	81.05	silver quality
epithelial cell of pancreas	CL:0000083	80.83	gold quality
pancreatic ductal cell	CL:0002079	79.65	silver quality
epithelium of esophagus	UBERON:0001976	78.94	gold quality
germinal epithelium of ovary	UBERON:0001304	78.57	gold quality
parietal pleura	UBERON:0002400	78.47	gold quality
adrenal tissue	UBERON:0018303	78.30	gold quality
islet of Langerhans	UBERON:0000006	78.11	gold quality
ileal mucosa	UBERON:0000331	77.46	gold quality
smooth muscle tissue	UBERON:0001135	76.61	gold quality
tendon	UBERON:0000043	76.41	gold quality
pleura	UBERON:0000977	76.26	gold quality
endometrium	UBERON:0001295	76.23	gold quality
oral cavity	UBERON:0000167	75.57	gold quality
nasal cavity epithelium	UBERON:0005384	74.53	silver quality
urinary bladder	UBERON:0001255	74.25	gold quality
visceral pleura	UBERON:0002401	74.00	gold quality
colonic mucosa	UBERON:0000317	73.87	gold quality
right adrenal gland cortex	UBERON:0035827	73.77	gold quality
left adrenal gland	UBERON:0001234	73.69	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.06

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
LGALS9	Activation

Upstream regulators (CollecTRI, top): AIRE, E2F1, IRF1, IRF3, IRF6, IRF8, NFKB1, RELA, SSRP1, STAT1, TP53

miRNA regulators (miRDB)

21 targeting TLR3, 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-4776-3P	100.00	68.73	1340
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-8070	99.07	69.30	1303
HSA-MIR-3142	98.88	66.09	529
HSA-MIR-1245B-5P	98.88	66.55	576
HSA-MIR-5590-5P	98.81	68.78	969
HSA-MIR-5197-3P	98.71	67.05	1905
HSA-MIR-384	98.71	67.34	1229
HSA-MIR-5571-3P	97.80	66.07	640
HSA-MIR-3121-5P	97.30	66.62	1146
HSA-MIR-1225-5P	96.76	66.85	417
HSA-MIR-1295B-3P	96.68	66.11	276
HSA-MIR-7975	95.04	66.76	516
HSA-MIR-1229-5P	94.57	65.78	487

Literature-anchored findings (GeneRIF, showing 40)

• the first demonstration of the importance of TLR3 cytoplasmic tyrosine residues in double-stranded RNA signaling (PMID:12509442)
• TLR3 has a role in innate and adaptive immune responses (PMID:12672806)
• TLR4-mediated activation of the interferon-sensitive response element has an absolute requirement for NFKBp65, whereas the TLR3-induced ISRE response is NFKB-independent (PMID:14557267)
• measles virus-induced expression of TLR3 may reflect amplified IFN production that plays a part in host defense to viral infection (PMID:14575692)
• RNA, likely through secondary structure, is a potent host-derived activator of TLR3 (PMID:14729660)
• double-stranded RNA-induced TLR3/TRIF-mediated NF-kappaB and IRF3 activation diverge at TRIF (PMID:14982987)
• This isoform has 2,520 bp cDNAs compared to the 2,712 bp of full cDNA, is produced by deletion of an intron-like sequence within exon 4 and is co-expressed with wild type TLR3 in primary human astrocytes and glioblastoma cell lines. (PMID:15119015)
• siRNA and shRNA knockdown of genes represents a new and powerful tool, it is not without nonspecific effects, which we demonstrate are mediated in part by signaling through TLR3. (PMID:15153468)
• Data support the hypothesis that toll-like receptor-3 is an important determinant of cellular responses to external double-stranded RNA. (PMID:15212709)
• the cytoplasmic linker region of TLR3 regulates receptor retention inside the organelle and signaling (PMID:15226270)
• With expression of TLR3, poly I:C stimulation induces the activation of interferon regulatory factor-3. (PMID:15315972)
• dsRNA-activated phosphorylation of two specific tyrosine residues of TLR3 is essential for initiating two distinct signaling pathways (PMID:15502848)
• TLR3 is constitutively expressed in human alveolar and bronchial epithelial cells; TLR3 contributes directly to the immune response of respiratory epithelial cells to influenza A virus and dsRNA (PMID:15579900)
• Resting and activated human astrocytes preferentially express TLR3, constitutively express adapters linked to TLR3 signaling, and respond to TLR3 engagement with production of TNF-alpha, IL-6, and chemokines. (PMID:15652398)
• studies indicate that TLR3 mediates inflammatory cytokine and chemokine production in respiratory syncytial virus-infected epithelial cells. (PMID:15731229)
• hepatocytes contain two distinct antiviral signaling pathways leading to expression of intereron beta, one dependent upon TLR3 and the other dependent on RIG-I, with little cross-talk between these pathways (PMID:15737993)
• Toll-like receptor 3, although essential for gene induction by dsRNA, was dispensable for gene induction by Sendai virus (PMID:15767394)
• IFN-alpha-induced up-regulation of TLR3 expression is involved in dsRNA activated antiviral response in human epithelial and endothelial cells (PMID:15778392)
• The gene expression and surface expression of TLR3 in polyI:C-stimulated corneal epithelial cells. (PMID:15845391)
• TLR3 is involved in the immune responses of endometrial epithelial cells after exposure to dsRNA and has the potential to alter the cytokine milieu and influence the outcome and consequences of infection. (PMID:15935884)
• crystal structure of ectodomain; large horseshoe-shaped solenoid assembled from 23 leucine-rich repeats (LRRs) (PMID:15961631)
• TLR3 and TLR4 signal primarily through NF-kappaB to enhance transcription of pIgR mRNA. (PMID:15972671)
• These results suggest that polymorphisms in the TLR3 gene, which is part of the innate immune system, may be associated with type 1 diabetes in this population. (PMID:16029432)
• Biliary epithelial cell antibodies via induction of TLR2 and TLR3, as well as inflammatory cytokine and chemokine production may induce epithelial cell inflammatory responses to bacterial components and contribute to posttransplantation cholangitis. (PMID:16035096)
• The overall horseshoe-shaped structure of the TLR3-ectodomain is formed by 23 repeating leucine-rich repeats (LRRs) that are capped at each end by specialized non-LRR domains. (PMID:16043704)
• TLR3 engagement by poly(I-C) at an acidic pH, probably in early phagolysosomes or endosomes, induces receptor aggregation leading to signaling (PMID:16144834)
• The up-regulation of Toll-like receptors 2, 3 and 4 in the nasal mucosa of patients with symptomatic allergic rhinitis supports the idea of a role for Toll-like receptors in allergic airway inflammation. (PMID:16146574)
• This study demonstrates an important functional requirement for TLR3 in the host response against rhinovirus infection (PMID:16160153)
• required for the activation of NFkappaB by the LTRf from Moloney murine and feline leukemia viruses (PMID:16289658)
• The role of TLR3 in the immunobiology of muscle is reported; its implications for the understanding of the pathogenesis of inflammatory myopathies or therapeutic interventions are included. (PMID:16293707)
• Exposure of respiratory epithelial cells to diesel exhause enhances virus and could potentially alter the response to viral infections by increasing the expression and function of TLR3. (PMID:16399790)
• Respiratory syncytial virus, via an effect on TLR3 and protein kinase R, sensitizes airway epithelial cells to subsequent double-stranded (ds)RNA exposure. (PMID:16424203)
• TLR3 is induced on human astrocytes upon inflammation and when activated, mediates a comprehensive neuroprotective response rather than a polarized pro-inflammatory reaction. (PMID:16482523)
• the interaction of IRF-8 with TRAF6 modulates TLR signaling and may contribute to the cross-talk between IFN-gamma and TLR signal pathways (PMID:16484229)
• analysis of glycosylation of human Toll-like receptor 3 (PMID:16533755)
• direct proapoptotic activity of endogenous TLR3 expressed by cancerous cells (PMID:16585585)
• the STAT1-SOCS1 pathway regulates the innate immune response via TLR3 signaling in epidermal keratinocytes (PMID:16628196)
• These mutations locate the dsRNA binding site on the glycan-free, lateral surface of TLR3 toward the C terminus and suggest a model for dsRNA binding and TLR3 activation. (PMID:16720699)
• findings demonstrate that TLR-3 and TLR-9 mediate the activation of corneal cells by Herpes simplex virus 1, HSV-1 DNA and HSV-1-antibody complexes (PMID:16847112)
• TLR3 associates with activated c-Src tyrosine kinase double-stranded (ds)RNA-containing endosomes in HeLa cells, and triggers an innate immune response during viral infection. (PMID:16858407)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	lrrc15	ENSDARG00000070792
mus_musculus	Tlr3	ENSMUSG00000031639
rattus_norvegicus	Tlr3	ENSRNOG00000021726

Paralogs (22): IGFALS (ENSG00000099769), TLR8 (ENSG00000101916), LRRC17 (ENSG00000128606), RXFP2 (ENSG00000133105), CD180 (ENSG00000134061), TLR4 (ENSG00000136869), TLR2 (ENSG00000137462), LRRC32 (ENSG00000137507), LRRC3 (ENSG00000160233), LRRC53 (ENSG00000162621), VASN (ENSG00000168140), RXFP1 (ENSG00000171509), NRROS (ENSG00000174004), TLR10 (ENSG00000174123), TLR1 (ENSG00000174125), TLR6 (ENSG00000174130), LRRC3B (ENSG00000179796), TSKU (ENSG00000182704), TLR5 (ENSG00000187554), TLR7 (ENSG00000196664), LRIT2 (ENSG00000204033), LRRC3C (ENSG00000204913)

Protein

Protein identifiers

Toll-like receptor 3 — O15455 (reviewed: O15455)

All UniProt accessions (4): A0A8V8TLN9, A0A8V8TN43, D6RA51, O15455

UniProt curated annotations — full annotation on UniProt →

Function. Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR3 is a nucleotide-sensing TLR which is activated by double-stranded RNA, a sign of viral infection. Acts via the adapter TRIF/TICAM1, leading to NF-kappa-B activation, IRF3 nuclear translocation, cytokine secretion and the inflammatory response.

Subunit / interactions. Monomer and homodimer; dimerization is triggered by ligand-binding, the signaling unit is composed of one ds-RNA of around 40 bp and two TLR3 molecules, and lateral clustering of signaling units along the length of the ds-RNA ligand is required for TLR3 signal transduction. Interacts (via transmembrane domain) with UNC93B1; the interaction is required for transport from the ER to the endosomes. Interacts with SRC; upon binding of double-stranded RNA. Interacts with TICAM1 (via the TIR domain) in response to poly(I:C) and this interaction is enhanced in the presence of WDFY1. The tyrosine-phosphorylated form (via TIR domain) interacts with WDFY1 (via WD repeat 2) in response to poly(I:C).

Subcellular location. Endoplasmic reticulum membrane. Endosome membrane. Early endosome.

Tissue specificity. Expressed at high level in placenta and pancreas. Also detected in CD11c+ immature dendritic cells. Only expressed in dendritic cells and not in other leukocytes, including monocyte precursors. TLR3 is the TLR that is expressed most strongly in the brain, especially in astrocytes, glia, and neurons.

Post-translational modifications. Heavily N-glycosylated, except on that part of the surface of the ectodomain that is involved in ligand binding. TLR3 signaling requires a proteolytic cleavage mediated by cathepsins CTSB and CTSH, the cleavage occurs between amino acids 252 and 346. The cleaved form of TLR3 is the predominant form found in endosomes. Ubiquitinated by TRIM3; leading to recognition and sorting of polyubiquitinated TLR3 by the ESCRT complexes. Ubiquitinated by ZNRF1 via ‘Lys-63’-linked ubiquitin chains; leading to TLR3 lysosomal trafficking and degradation. Ubiquitinated by RNF170 at Lys-765 via ‘Lys-48’-linked ubiquitin chains; leading to TLR3 proteasomal degradation.

Disease relevance. Immunodeficiency 83, susceptibility to viral infections (IMD83) [MIM:613002] An immunologic disorder characterized by increased susceptibility to severe viral infections, including herpes simplex virus (HSV), varicella zoster virus (VZV), influenza A virus (IAV), hantavirus, and possibly respiratory syncytial virus (RSV). IMD83 clinical manifestations include acute infection-induced encephalitis and pneumonitis. The susceptibility to encephalitis or pneumonitis appears to result from impaired TLR3-dependent interferon production by nonhematopoietic cells that reside within the central nervous system or lung epithelial cells. IMD83 transmission pattern is consistent with autosomal dominant or autosomal recessive inheritance with incomplete penetrance. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. ds-RNA binding is mediated by LRR 1 to 3, and LRR 17 to 18.

Polymorphism. The Phe-412 allele (dbSNP:rs3775291) occurs with a frequency of 30% in populations with European and Asian ancestry, and confers some natural resistance to HIV-1 infection.

Similarity. Belongs to the Toll-like receptor family.

Isoforms (2)

UniProt ID	Names	Canonical?
O15455-1	1	yes
O15455-2	2

RefSeq proteins (1): NP_003256* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000157	TIR_dom	Domain
IPR000483	Cys-rich_flank_reg_C	Domain
IPR001611	Leu-rich_rpt	Repeat
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR035897	Toll_tir_struct_dom_sf	Homologous_superfamily
IPR041015	TLR3_TMD	Domain

Pfam: PF01582, PF13516, PF13855, PF17968

UniProt features (160 total): strand 43, repeat 22, turn 19, helix 16, glycosylation site 15, sequence variant 12, mutagenesis site 11, disulfide bond 4, sequence conflict 4, domain 3, cross-link 3, topological domain 2, modified residue 2, signal peptide 1, chain 1, transmembrane region 1, splice variant 1

Structure

Experimental structures (PDB)

20 structures.

PDB	Method	Resolution (Å)
1ZIW	X-RAY DIFFRACTION	2.1
7WV3	ELECTRON MICROSCOPY	2.26
2A0Z	X-RAY DIFFRACTION	2.4
8YHT	ELECTRON MICROSCOPY	2.88
8YHU	ELECTRON MICROSCOPY	2.88
7WV5	ELECTRON MICROSCOPY	3.1
9LSJ	ELECTRON MICROSCOPY	3.1
7WVE	ELECTRON MICROSCOPY	3.11
7WVJ	ELECTRON MICROSCOPY	3.26
5GS0	X-RAY DIFFRACTION	3.27
9LSI	ELECTRON MICROSCOPY	3.3
7WV4	ELECTRON MICROSCOPY	3.35
7C76	ELECTRON MICROSCOPY	3.4
3ULU	X-RAY DIFFRACTION	3.52
3ULV	X-RAY DIFFRACTION	3.52
9LSH	ELECTRON MICROSCOPY	3.8
7WVF	ELECTRON MICROSCOPY	3.91
2MK9	SOLUTION NMR
2MKA	SOLUTION NMR
8AR1	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15455-F1	90.64	0.74

Antibody-complex structures (SAbDab): 4 — 3ULU, 3ULV, 5GS0, 7WVF

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 (5): 759, 858, 765, 812, 831

Disulfide bonds (4): 28–37, 95–122, 649–677, 651–696

Glycosylation sites (15): 52, 57, 70, 124, 196, 247, 252, 265, 275, 291, 398, 413, 507, 636, 662

Mutagenesis-validated functional residues (11):

Position	Phenotype
95	reduced response to ds-rna.
122	reduced response to ds-rna.
196	reduced expression levels; when associated with r-247.
247	reduced response to ds-rna. reduced expression levels; when associated with g-196.
539	no effect.
539	loss of rna binding. constitutive activation of nf-kappa-b.
541	loss of rna binding. abolishes activation of nf-kappa-b.
759	reduced activation of nf-kappa-b in response to ds-rna. reduced induction of il-8 in response to ds-rna. loss of interac
812	loss of ubiquitination by znrf1.
831	loss of ubiquitination by trim3.
858	loss of interaction with wdfy1.

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-1679131	Trafficking and processing of endosomal TLR
R-HSA-168164	Toll Like Receptor 3 (TLR3) Cascade
R-HSA-168927	TICAM1, RIP1-mediated IKK complex recruitment
R-HSA-1810476	RIP-mediated NFkB activation via ZBP1
R-HSA-5602410	TLR3 deficiency - HSE
R-HSA-5602415	UNC93B1 deficiency - HSE
R-HSA-5602566	TICAM1 deficiency - HSE
R-HSA-5602571	TRAF3 deficiency - HSE
R-HSA-9013957	TLR3-mediated TICAM1-dependent programmed cell death
R-HSA-9013973	TICAM1-dependent activation of IRF3/IRF7
R-HSA-9014325	TICAM1,TRAF6-dependent induction of TAK1 complex
R-HSA-9828211	Regulation of TBK1, IKKε-mediated activation of IRF3, IRF7 upon TLR3 ligation
R-HSA-9833110	RSV-host interactions

MSigDB gene sets: 477 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_CELLULAR_RESPONSE_TO_VIRUS, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, LU_IL4_SIGNALING, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, GOBP_INFLAMMATORY_RESPONSE, GOBP_POSITIVE_REGULATION_OF_INTERLEUKIN_8_PRODUCTION, GOCC_VACUOLAR_MEMBRANE, FISCHER_G1_S_CELL_CYCLE, GOBP_CELLULAR_RESPONSE_TO_EXTERNAL_STIMULUS, MODULE_64

GO Biological Process (54): microglial cell activation (GO:0001774), toll-like receptor signaling pathway (GO:0002224), regulation of dendritic cell cytokine production (GO:0002730), hyperosmotic response (GO:0006972), signal transduction (GO:0007165), activation of NF-kappaB-inducing kinase activity (GO:0007250), JNK cascade (GO:0007254), male gonad development (GO:0008584), detection of virus (GO:0009597), positive regulation of gene expression (GO:0010628), positive regulation of chemokine production (GO:0032722), positive regulation of interferon-alpha production (GO:0032727), positive regulation of interferon-beta production (GO:0032728), positive regulation of type II interferon production (GO:0032729), positive regulation of interleukin-12 production (GO:0032735), 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), toll-like receptor 3 signaling pathway (GO:0034138), type III interferon production (GO:0034343), positive regulation of type III interferon production (GO:0034346), cellular response to interferon-beta (GO:0035458), defense response to bacterium (GO:0042742), positive regulation of apoptotic process (GO:0043065), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), response to exogenous dsRNA (GO:0043330), response to dsRNA (GO:0043331), innate immune response (GO:0045087), negative regulation of osteoclast differentiation (GO:0045671), positive regulation of angiogenesis (GO:0045766), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of JNK cascade (GO:0046330), positive regulation of inflammatory response (GO:0050729), defense response to virus (GO:0051607), positive regulation of macrophage cytokine production (GO:0060907), cellular response to mechanical stimulus (GO:0071260), cellular response to type II interferon (GO:0071346), cellular response to exogenous dsRNA (GO:0071360), cellular response to xenobiotic stimulus (GO:0071466), inflammatory response to wounding (GO:0090594)

GO Molecular Function (8): double-stranded RNA binding (GO:0003725), transmembrane signaling receptor activity (GO:0004888), signaling receptor activity (GO:0038023), pattern recognition receptor activity (GO:0038187), identical protein binding (GO:0042802), ubiquitin-like protein ligase binding (GO:0044389), RNA binding (GO:0003723), protein binding (GO:0005515)

GO Cellular Component (11): Golgi membrane (GO:0000139), cytoplasm (GO:0005737), lysosomal membrane (GO:0005765), early endosome (GO:0005769), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), endosome membrane (GO:0010008), membrane (GO:0016020), endolysosome membrane (GO:0036020), endosome (GO:0005768), endoplasmic reticulum (GO:0005783)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Toll Like Receptor 3 (TLR3) Cascade	4
Diseases associated with the TLR signaling cascade	4
Toll-like Receptor Cascades	2
ZBP1(DAI) mediated induction of type I IFNs	1
TICAM1-dependent activation of IRF3/IRF7	1
Respiratory Syncytial Virus Infection Pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of cytokine production	5
positive regulation of type I interferon production	2
signaling receptor activity	2
bounding membrane of organelle	2
cellular anatomical structure	2
endosome	2
endomembrane system	2
leukocyte activation involved in inflammatory response	1
macrophage activation	1
glial cell activation	1
pattern recognition receptor signaling pathway	1
dendritic cell cytokine production	1
regulation of leukocyte mediated immunity	1
regulation of cytokine production involved in immune response	1
response to osmotic stress	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
activation of protein kinase activity	1
non-canonical NF-kappaB signal transduction	1
MAPK cascade	1
gonad development	1
development of primary male sexual characteristics	1
response to virus	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
chemokine production	1
regulation of chemokine production	1
interferon-alpha production	1
regulation of interferon-alpha production	1
interferon-beta production	1
regulation of interferon-beta production	1
type II interferon production	1
regulation of type II interferon production	1
interleukin-12 production	1
regulation of interleukin-12 production	1
interleukin-6 production	1

Protein interactions and networks

STRING

4212 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TLR3	MYD88	P78397	999
TLR3	TICAM1	Q8IUC6	997
TLR3	UNC93B1	Q9H1C4	995
TLR3	IFNB1	P01574	995
TLR3	TRAF3	Q13114	981
TLR3	TIRAP	P58753	980
TLR3	IFIH1	Q9BYX4	970
TLR3	TBK1	Q9UHD2	969
TLR3	RIGI	O95786	968
TLR3	IRF3	Q14653	959
TLR3	IKBKE	Q14164	956
TLR3	HMGB1	P09429	952
TLR3	TLR7	Q9NYK1	939
TLR3	RIPK3	Q9Y572	926
TLR3	MAVS	Q7Z434	913

IntAct

27 interactions, top by confidence:

A	B	Type	Score
TLR3	TLR3	psi-mi:“MI:0915”(physical association)	0.740
TLR3	TLR3	psi-mi:“MI:0407”(direct interaction)	0.740
PIK3R1	TLR3	psi-mi:“MI:0915”(physical association)	0.520
TLR3	TRIL	psi-mi:“MI:0915”(physical association)	0.460
TRIL	TLR3	psi-mi:“MI:0403”(colocalization)	0.460
TLR3	SRC	psi-mi:“MI:0915”(physical association)	0.460
SRC	TLR3	psi-mi:“MI:0403”(colocalization)	0.460
TLR3	MBL2	psi-mi:“MI:0915”(physical association)	0.460
TLR3	MBL2	psi-mi:“MI:0403”(colocalization)	0.460
TLR3	UNC93B1	psi-mi:“MI:0915”(physical association)	0.400
SIGLEC5	TLR3	psi-mi:“MI:0915”(physical association)	0.400
SIGLEC6	TLR3	psi-mi:“MI:0915”(physical association)	0.400
SIGLEC7	TLR3	psi-mi:“MI:0915”(physical association)	0.400
SIGLEC9	TLR3	psi-mi:“MI:0915”(physical association)	0.400
SIGLEC10	TLR3	psi-mi:“MI:0915”(physical association)	0.400
SIGLEC11	TLR3	psi-mi:“MI:0915”(physical association)	0.400
CFTR	TLR3	psi-mi:“MI:0915”(physical association)	0.370
TLR3	CHEK2	psi-mi:“MI:0915”(physical association)	0.370
TLR3	BLK	psi-mi:“MI:0914”(association)	0.350
AFG2A	ESYT2	psi-mi:“MI:0914”(association)	0.350
TLR3	TRAF3	psi-mi:“MI:0914”(association)	0.350
CLGN	TMEM131L	psi-mi:“MI:0914”(association)	0.350

BioGRID (66): TLR3 (Two-hybrid), HLA-DRA (Affinity Capture-Western), HLA-DRA (FRET), TICAM1 (Affinity Capture-Western), WDFY1 (Affinity Capture-Western), TLR3 (Affinity Capture-Western), TICAM1 (Affinity Capture-Western), RIPK1 (Affinity Capture-Western), TBK1 (Affinity Capture-Western), RNF31 (Affinity Capture-Western), SHARPIN (Affinity Capture-Western), CASP8 (Affinity Capture-Western), FADD (Affinity Capture-Western), RBCK1 (Affinity Capture-Western), IKBKG (Affinity Capture-Western)

ESM2 similar proteins: A3KNN3, A6H789, A8WHP9, C3YZ59, D3ZTV3, O00206, O08680, O15455, O43155, O60602, O73875, P06213, P08953, P15127, P15208, P54755, P54756, P54757, P58682, P58727, Q0PV50, Q2V898, Q504C1, Q5R7M3, Q5RAC4, Q5TJ59, Q68Y56, Q6R5N8, Q7TNJ4, Q80ZD9, Q810C1, Q86SJ2, Q8BZT5, Q8SPE8, Q8SPE9, Q8SXT3, Q8VCH9, Q96PB8, Q96PX8, Q99MB1

Diamond homologs: O15455, P58682, Q0PV50, Q5TJ59, Q6QNU9, Q6R5N8, Q99MB1, Q9NR97, Q9R1B9, Q9WVC1, D3ZTV3, F1NUK7, O43155, O46379, P23515, P28654, P51884, P51885, P51886, P51890, P58681, Q01129, Q05443, Q2EEY0, Q5I2M3, Q5I2M4, Q5I2M5, Q5I2M7, Q5I2M8, Q5M7S9, Q5S006, Q63912, Q68CR7, Q8BLU0, Q9C8K0, Q9CQ76, Q9DE67, Q9EQU3, Q9LMP6, Q9NR96

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
STAT1	“up-regulates quantity by expression”	TLR3	“transcriptional regulation”
EGFR	“up-regulates activity”	TLR3	phosphorylation
SRC	“up-regulates activity”	TLR3	phosphorylation
E2F1	“down-regulates quantity by repression”	TLR3	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 19 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
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	5	31.1×	8e-05
Adaptive Immune System	6	12.8×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
cell adhesion	7	13.8×	8e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	397
Likely benign	161
Benign	17

Top pathogenic / likely-pathogenic (0)

SpliceAI

813 predictions. Top by Δscore:

Variant	Effect	Δscore
4:186069229:A:T	donor_gain	1.0000
4:186069248:AGTA:A	donor_loss	1.0000
4:186069249:G:GG	donor_gain	1.0000
4:186069249:GTAA:G	donor_loss	1.0000
4:186069250:T:G	donor_loss	1.0000
4:186076611:A:AG	acceptor_gain	1.0000
4:186076612:G:GG	acceptor_gain	1.0000
4:186076612:GC:G	acceptor_gain	1.0000
4:186076612:GCA:G	acceptor_gain	1.0000
4:186076612:GCAGA:G	acceptor_gain	1.0000
4:186078839:GA:G	acceptor_gain	1.0000
4:186082318:A:AG	acceptor_gain	1.0000
4:186082319:G:GG	acceptor_gain	1.0000
4:186069244:TCCAA:T	donor_gain	0.9900
4:186069245:CCAA:C	donor_gain	0.9900
4:186069247:AA:A	donor_gain	0.9900
4:186076610:C:G	acceptor_gain	0.9900
4:186078836:TCA:T	acceptor_loss	0.9900
4:186078836:TCAGA:T	acceptor_gain	0.9900
4:186078837:CA:C	acceptor_loss	0.9900
4:186078837:CAG:C	acceptor_gain	0.9900
4:186078838:A:AG	acceptor_gain	0.9900
4:186078838:AG:A	acceptor_loss	0.9900
4:186078838:AGAAT:A	acceptor_gain	0.9900
4:186078839:G:GA	acceptor_loss	0.9900
4:186078839:G:GG	acceptor_gain	0.9900
4:186078839:GAAT:G	acceptor_gain	0.9900
4:186078839:GAATT:G	acceptor_gain	0.9900
4:186079029:GAG:G	donor_gain	0.9900
4:186079030:AG:A	donor_loss	0.9900

AlphaMissense

6030 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:186083715:T:A	C677S	0.997
4:186083716:G:C	C677S	0.997
4:186083546:T:A	N620K	0.996
4:186083546:T:G	N620K	0.996
4:186083621:T:A	N645K	0.996
4:186083621:T:G	N645K	0.996
4:186083631:T:C	C649R	0.996
4:186083322:T:A	W546R	0.995
4:186083322:T:C	W546R	0.995
4:186083631:T:A	C649S	0.995
4:186083632:G:C	C649S	0.995
4:186083633:C:G	C649W	0.995
4:186083715:T:C	C677R	0.995
4:186083716:G:A	C677Y	0.995
4:186083536:T:C	L617P	0.994
4:186083632:G:A	C649Y	0.994
4:186083717:C:G	C677W	0.994
4:186076874:C:A	N85K	0.993
4:186076874:C:G	N85K	0.993
4:186083306:C:A	N540K	0.993
4:186083306:C:G	N540K	0.993
4:186084661:G:C	A835P	0.992
4:186076792:T:C	L58P	0.991
4:186083386:T:C	L567P	0.991
4:186083716:G:T	C677F	0.991
4:186084114:A:C	S810R	0.991
4:186084116:C:A	S810R	0.991
4:186084116:C:G	S810R	0.991
4:186076786:T:C	L56S	0.990
4:186076802:T:A	N61K	0.990

dbSNP variants (sampled 300 via entrez): RS1000030704 (4:186072382 G>A,C), RS1000196279 (4:186078078 G>A), RS1000289578 (4:186068906 G>A), RS1000362185 (4:186074828 T>A), RS1000396838 (4:186075180 T>C), RS1000567262 (4:186076009 C>A,T), RS1000596230 (4:186067471 G>C), RS1000775304 (4:186075689 T>A,C), RS1000794714 (4:186073632 T>C), RS1000815483 (4:186079857 G>A), RS1001059746 (4:186086281 G>C), RS1001142171 (4:186073882 A>C), RS1001149000 (4:186078283 G>A), RS1001178279 (4:186078798 A>G), RS1001355502 (4:186084668 A>C,G)

Disease associations

OMIM: gene MIM:603029 | disease phenotypes: MIM:610551, MIM:613002, MIM:609423, MIM:609532

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 83, susceptibility to viral infections	Strong	Autosomal dominant

Mondo (4): herpes simplex encephalitis, susceptibility to, 1 (MONDO:0024563), immunodeficiency 83, susceptibility to viral infections (MONDO:0800187), susceptibility to HIV infection (MONDO:0004951), hepatitis C virus, susceptibility to (MONDO:0012292)

Orphanet (1): Herpes simplex virus encephalitis (Orphanet:1930)

HPO phenotypes

42 total (30 of 42 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001254	Lethargy
HP:0001259	Coma
HP:0001262	Excessive daytime somnolence
HP:0001268	Mental deterioration
HP:0001269	Hemiparesis
HP:0001287	Meningitis
HP:0001289	Confusion
HP:0001347	Hyperreflexia
HP:0001945	Fever
HP:0001974	Increased total leukocyte count
HP:0002017	Nausea and vomiting
HP:0002133	Status epilepticus
HP:0002167	Abnormal speech pattern
HP:0002171	Gliosis
HP:0002181	Cerebral edema
HP:0002315	Headache
HP:0002349	Focal aware seizure
HP:0002353	EEG abnormality
HP:0002384	Focal impaired awareness seizure
HP:0002721	Immunodeficiency
HP:0002902	Hyponatremia
HP:0002922	Increased CSF protein concentration
HP:0003621	Juvenile onset
HP:0003829	Typified by incomplete penetrance
HP:0004302	Functional motor deficit
HP:0004372	Reduced consciousness

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001585_37	Breast size	6.000000e-06
GCST007932_26	Medication use (thyroid preparations)	3.000000e-18
GCST010571_27	Autoimmune thyroid disease	7.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009933	Thyroid preparation use measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1075113 (SINGLE PROTEIN), CHEMBL4106182 (PROTEIN FAMILY)

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs3775291	Efficacy	3	Measles vaccines
rs3775291	Toxicity	3	aspirin	Asthma

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3775291	TLR3	3	2.25	2	Measles vaccines;aspirin

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — Toll-like receptor family

ChEMBL bioactivities

8 potent at pChembl≥5 of 11 total, top 7 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.96	IC50	110	nM	CHEMBL19954
5.67	IC50	2160	nM	CHEMBL4647818
5.62	IC50	2400	nM	CHEMBL4795714
5.53	Ki	2960	nM	CHEMBL4303728
5.46	IC50	3440	nM	CHEMBL4303728
5.32	EC50	4800	nM	CHEMBL4074408
5.26	IC50	5440	nM	CHEMBL4636498

PubChem BioAssay actives

8 with measured affinity, of 345 total; 6 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
9-methoxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazole	1984804: Inhibition of TLR3 in HEK-Blue hTLR3 assessed as inhibition of poly (I:C) induced SEAP signalling	ic50	0.1100	uM
2-[4-[2-(3,4-dimethoxyphenyl)-3-methyl-1H-indol-5-yl]piperidin-1-yl]-N-methylethanamine	1662073: Antagonist activity at human TLR3 overexpressed in HEK-Blue cells assessed as inhibition of Poly IC-induced NFkappaB and AP-1 activation preincubated for 30 mins followed by Poly IC stimulation measured after 22 hrs by quanti-blue SEAP assay	ic50	2.1600	uM
1-pentyl-4-(2-phenylmethoxyphenyl)imidazol-2-amine;hydrochloride	1734126: Inhibition of human TLR3 stably expressed in HEK293 cells cotransfected with secreted alkaline phosphatase assessed as assessed as inhibition of poly(I/C)-induced NF-kappaB activation by quanti-blue SEAP reporter gene based spectrophotometric method	ic50	2.4000	uM
(2R)-2-[(3-chloro-6-fluoro-1-benzothiophene-2-carbonyl)amino]-3-phenylpropanoic acid	1989271: Binding affinity to TLR3 (unknown origin) assessed as inhibition constant	ki	2.9600	uM
6,7-bis[(4-nitrophenyl)methoxy]spiro[chromene-2,4’-oxane]	1448645: Agonist activity at human TLR3 expressed in HEK293 cells assessed as induction of NF-kB activation-mediated SEAP production after 24 hrs by HTS assay	ec50	4.8000	uM
2-[4-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]-N-methylethanamine	1662073: Antagonist activity at human TLR3 overexpressed in HEK-Blue cells assessed as inhibition of Poly IC-induced NFkappaB and AP-1 activation preincubated for 30 mins followed by Poly IC stimulation measured after 22 hrs by quanti-blue SEAP assay	ic50	5.4400	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Poly I-C	increases reaction, affects reaction, increases activity, affects binding, affects cotreatment (+4 more)	12
Valproic Acid	affects cotreatment, increases expression, decreases expression	5
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	4
Acetaminophen	increases expression, decreases expression, affects cotreatment	4
Cyclosporine	increases expression	4
Triclosan	affects cotreatment, increases expression, decreases expression	3
Particulate Matter	increases abundance, increases expression, affects reaction, decreases expression	3
bisphenol A	decreases expression, increases methylation, affects cotreatment, increases expression	2
perfluorooctanoic acid	decreases expression	2
potassium chromate(VI)	affects cotreatment, decreases expression	2
epigallocatechin gallate	increases expression, affects cotreatment, decreases expression	2
monomethylarsonous acid	increases expression, decreases expression	2
(+)-JQ1 compound	decreases expression	2
Air Pollutants	decreases expression, increases abundance	2
Calcitriol	increases expression, affects cotreatment	2
Dexamethasone	decreases expression, affects cotreatment, increases expression	2
Doxorubicin	decreases expression	2
Fluorouracil	increases expression, affects reaction	2
Lipopolysaccharides	increases expression, affects cotreatment, decreases expression	2
Ozone	affects cotreatment, decreases expression, increases expression	2
Silver	increases expression, decreases expression	2
Tretinoin	increases expression	2
Aflatoxin B1	increases expression, affects expression	2
bisphenol F	increases expression, affects cotreatment	1
sotorasib	affects cotreatment, increases expression	1
2-anisidine	decreases expression	1
1-aminopyrene	affects binding, affects response to substance	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
6-hydroxy-5-((p- sulfophenyl)azo)-2-naphthalenesulfonic acid disodium salt	affects cotreatment, increases expression	1

ChEMBL screening assays

55 unique, capped per target: 52 binding, 3 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1102312	Binding	Activation of human TLR3 expressed in HEK293 assessed as induction of NF-kappaB activity reporter gene assay	Toll-like receptor 7 selective synthetic oligoribonucleotide agonists: synthesis and structure-activity relationship studies. — J Med Chem
CHEMBL2020651	Functional	Agonist activity at human TLR3 HEK-Blue cells assessed as increase in NFkappaB activation by sAP reporter gene assay	Toll-like receptor (TLR)-7 and -8 modulatory activities of dimeric imidazoquinolines. — J Med Chem

Cellosaurus cell lines

24 cell lines: 18 transformed cell line, 5 cancer cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A8CL	HEK-Blue IL-1beta	Transformed cell line	Female
CVCL_A8CM	HEK-Blue IL-1R	Transformed cell line	Female
CVCL_A8CQ	HEK-Blue-Lucia Null (NF/IL8)	Transformed cell line	Female
CVCL_A8CR	HEK-Blue-Lucia hTLR2 (NF/IL8)	Transformed cell line	Female
CVCL_A8CS	HEK-Blue-Lucia hTLR3 (NF/IL8)	Transformed cell line	Female
CVCL_A8CT	HEK-Blue-Lucia hTLR5 (NF/IL8)	Transformed cell line	Female
CVCL_A8CU	HEK-Blue-Lucia hTLR9 (NF/IL8)	Transformed cell line	Female
CVCL_A8CV	HEK-Blue-Lucia mTLR4 (NF/IL8)	Transformed cell line	Female
CVCL_A8CW	HEK-Blue-Lucia mTLR7 (NF/IL8)	Transformed cell line	Female
CVCL_B8QY	Abcam HCT 116 TLR3 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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