TLR6

Summary

TLR6 (toll like receptor 6, HGNC:16711) is a protein-coding gene on chromosome 4p14, encoding Toll-like receptor 6 (Q9Y2C9). Participates in the innate immune response to Gram-positive bacteria and fungi.

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 functionally interacts with toll-like receptor 2 to mediate cellular response to bacterial lipoproteins. A Ser249Pro polymorphism in the extracellular domain of the encoded protein may be associated with an increased of asthma is some populations.

Source: NCBI Gene 10333 — RefSeq curated summary.

At a glance

• GWAS associations: 12
• Clinical variants (ClinVar): 99 total
• Druggable target: yes
• MANE Select transcript: NM_006068

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16711
Approved symbol	TLR6
Name	toll like receptor 6
Location	4p14
Locus type	gene with protein product
Status	Approved
Aliases	CD286
Ensembl gene	ENSG00000174130
Ensembl biotype	protein_coding
OMIM	605403
Entrez	10333

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000381950, ENST00000508254, ENST00000966018

RefSeq mRNA: 2 — MANE Select: NM_006068 NM_001394553, NM_006068

CCDS: CCDS3446

Canonical transcript exons

ENST00000508254 — 2 exons

Exon	Start	End
ENSE00002027927	38822897	38829537
ENSE00003532793	38856761	38856817

Expression profiles

Bgee: expression breadth ubiquitous, 157 present calls, max score 86.32.

FANTOM5 (CAGE): breadth broad, TPM avg 1.4257 / max 134.3853, expressed in 413 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
51814	1.4257	413
51815	0.1401	50

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	86.32	gold quality
mononuclear cell	CL:0000842	85.72	gold quality
leukocyte	CL:0000738	85.52	gold quality
blood	UBERON:0000178	83.83	gold quality
lymph node	UBERON:0000029	77.62	gold quality
granulocyte	CL:0000094	77.44	gold quality
spleen	UBERON:0002106	76.01	gold quality
vermiform appendix	UBERON:0001154	75.89	gold quality
bone marrow cell	CL:0002092	75.38	gold quality
calcaneal tendon	UBERON:0003701	74.76	gold quality
tonsil	UBERON:0002372	72.77	gold quality
tendon	UBERON:0000043	71.82	gold quality
gall bladder	UBERON:0002110	71.67	gold quality
caecum	UBERON:0001153	70.09	gold quality
bone marrow	UBERON:0002371	70.06	gold quality
stromal cell of endometrium	CL:0002255	69.99	gold quality
adrenal tissue	UBERON:0018303	68.64	gold quality
rectum	UBERON:0001052	67.93	gold quality
right lung	UBERON:0002167	67.54	gold quality
right adrenal gland cortex	UBERON:0035827	66.54	gold quality
smooth muscle tissue	UBERON:0001135	65.68	gold quality
tendon of biceps brachii	UBERON:0008188	65.45	silver quality
colonic epithelium	UBERON:0000397	65.43	silver quality
upper lobe of left lung	UBERON:0008952	65.30	gold quality
small intestine Peyer’s patch	UBERON:0003454	64.97	gold quality
right adrenal gland	UBERON:0001233	64.75	gold quality
left adrenal gland	UBERON:0001234	64.64	gold quality
minor salivary gland	UBERON:0001830	64.54	gold quality
adrenal gland	UBERON:0002369	64.53	gold quality
tongue squamous epithelium	UBERON:0006919	64.22	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.69

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
CCL5	Activation
CXCL1	Activation
CXCL2	Activation
IL1B	Activation

Upstream regulators (CollecTRI, top): HIF1A

Literature-anchored findings (GeneRIF, showing 40)

• stimulation by Mycoplasma fermentans lipoproteins mediates NF-kappa B activation as an early event and apoptosis as a later event in HEK293 cells (PMID:14706104)
• Toll-like receptor 2 dimerized with Toll-like receptor 6 or 1 is activated by saturated fatty acid and inhibited by polyunsaturated fatty acid (PMID:14966134)
• A function-blocking monoclonal antibody study reveals that human TLR6 recognizes diacylated lipopeptide MALP-2 and peptidoglycan at the monocyte cell surface cooperatively with human TLR2 receptor. (PMID:15661917)
• The observed multiple associated SNPs at the TLR6-TLR1-TLR10 gene cluster were dependent and suggest the presence of a founder prostate cancer risk variant on this haplotype background. (PMID:15812078)
• Subunit b of F0F1 type ATPase from Mycoplasma pneumoniae activates NF-kappaB through human TLR1, TLR2, and TLR6 (PMID:16177110)
• A Ser249Pro polymorphism in TLR6 might play a role in the pathogenesis of childhood asthma. (PMID:16188043)
• The presence of both TLR1 743A > G (Asn248 > Ser) and TLR6 745C > T (Ser249 > Pro) single nucleotide polymorphisms is associated with invasive aspergillosis following allogeneic stem cell transplantation. (PMID:16461792)
• TLR6 plays an important role in the regulation of the apoptosis of PMNs. Changes in the expression of TLR6 and inhibition of apoptosis of PMNs by rhIL-18 confirm the vital role this receptor and of rhIL-18 in regulating the survival of these cells. (PMID:16648973)
• TLR-2/6 and TLR2/1 heterodimer sorting at the cell surface determines heterotypic associations with CD36 and intracellular targeting (PMID:16880211)
• data suggest that TLR2/6 heterodimers are responsible for sensing Bacillus anthracis cell wall and PA, whereas the formation of the subsequent toxin (LF + PA) seems to evade detection by the innate immune system contributing to the virulence of the toxin. (PMID:17651447)
• No effect modification was observed for age, body mass index, or family history of prostate cancer, except that TLR6_3649 showed nominally significant interaction with family history at the P < 0.05 level. (PMID:17932345)
• The mean frequency of TLR-6 (toll-like receptor 6) expressing granulocytes in Behecets disease patients was significantly lower than in controls (PMID:17934735)
• Heterodimerization of TLR2 with TLR1 or TLR6 evolutionarily has developed to expand the ligand spectrum to enable the innate immune system to recognize the numerous, different structures of various bacterial lipopolysaccharides. (PMID:18056480)
• studies reveal coordinated induction of TLR2 and TLR6 during hypoxia and suggest tissue hypoxia in transcriptional adaptation of innate immune responses during acute infection or inflammation (PMID:18159247)
• TLR6 may be a key factor in determining whether the response to PDG would be apoptosis or inflammation. (PMID:18424724)
• The lipoproteins from U. parvum were found to activate NF-kappaB through TLR1, TLR2 and TLR6. (PMID:18451040)
• These results suggest that functional relevant TLR1 and TLR6 variants are directly involved in asthma development. (PMID:18547625)
• Human epidermal keratinocytes constitutively express all TLR 1-10 mRNA, which may enable human keratinocytes to respond to a wide range of pathogenic micro-organisms. (PMID:18686608)
• common haplotype in the TLR10-TLR1-TLR6 gene cluster influences prostate cancer risk and clearly supports the need for further investigation of TLR genes in other populations (PMID:18752252)
• infection of cells expressing toll-like receptors TLR2/6 with mycoplasma M. arginini leaded to suppression of apoptosis induced by chemotherapeutic agents (cisplatin, 5-fluorouracil, taxol). (PMID:19172872)
• plays a role in innate and adaptive immune responses. (review) (PMID:19378782)
• Wolbachia lipoprotein stimulates innate and adaptive immunity through Toll-like receptors 2 and 6 to induce disease manifestations of filariasis (PMID:19458089)
• Our results identify CD36-TLR4-TLR6 activation as a common molecular mechanism by which atherogenic lipids and amyloid-beta stimulate sterile inflammation (PMID:20037584)
• results clearly identified a TLR2/6-dependent induction of angiogenesis by the bacterial lipopeptide MALP-2, which is mediated by GM-CSF (PMID:20056792)
• Studies show substantial decreases in older compared with young individuals in cytokine production in response to TLR1/2, TLR6, TLR3, TLR5, and TLR8, TLR7 and TLR9 in DCs. (PMID:20100933)
• Common germ line genetic variation in TLR4 and TLR6-1-10 did not seem to have a strong association with risk of prostate cancer (PMID:20200442)
• These data suggest that hypertensive women homozygous for the TLR6 249Ser polymorphism might exhibit lower left ventricular wall thickness and reduced TLR6-mediated inflammatory response than females carrying the major allele. (PMID:20224557)
• TLR10 is most related to TLR1 and TLR6, both of which independently cooperate with TLR2 in the sensing of a variety of microbial and fungal components; TLR10 shares a number of microbial agonists with TLR1, but not TLR6, and uses TLR2 as a coreceptor. (PMID:20348427)
• In 191 in Chinese Cantonese persons, 7 single nucleotide polymorphisms were detected. Comparing these with the NCBI dbSNP database, 2 new SNPs (+176T/C & +1408G/T) & 5 SNPs causing amino-acid substitutions were reported. (PMID:20402822)
• These studies provide new insight into the role of TLR6 variation and the innate immune response to human infection. (PMID:20445564)
• The rs5743810 polymorphism of TLR6 may be involved in development of anti-interferon-beta antibodies in males, although further studies are required to firmly establish this. (PMID:20595247)
• A novel mechanism of lipoteichoic acid (LTA)-induced cytokine induction in human peripheral blood cells involves uptake of LTA and subsequent intracellular recognition driven by TLR2, TLR6, and CD14. (PMID:20713893)
• genetic polymorphism association with allergic rhinitis in asthma in a Chinese population (PMID:20815312)
• Toll-like receptors (TLRs) 6, 7, and 8 are upregulated in keloid scars (PMID:21677671)
• our data indicated a critical role for TLR6-dependent signaling in Mycobacterium leprae-Schwann cell interactions (PMID:21813774)
• TLR1/6 polymorphisms modulate TH1 T-cell polarization through genetic regulation of monocyte IL-10 secretion in the absence of IL-12. (PMID:21852947)
• study showed that coactivation of TLR4 and TLR2/6 coordinates an additive augmentation of IL-6 gene transcription via p38MAPK pathway in U937 mononuclear cells (PMID:22030478)
• Single nucleotide polymorphisms in TLR6 gene is associated with the inverse association between childhood acute lymphoblastic leukemia and atopic disease. (PMID:22134717)
• absence of the common haplotype in the TLR10-TLR1-TLR6 gene cluster increases the risk of developing chronic disease in patients already affected by sarcoidosis. (PMID:22150367)
• No TLR6 polymorphisms were detected in Korean subjects. (PMID:22219617)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tlr1	ENSDARG00000100649
mus_musculus	Tlr6	ENSMUSG00000051498
rattus_norvegicus	Tlr6	ENSRNOG00000002161

Paralogs (22): IGFALS (ENSG00000099769), TLR8 (ENSG00000101916), LRRC17 (ENSG00000128606), RXFP2 (ENSG00000133105), CD180 (ENSG00000134061), TLR4 (ENSG00000136869), TLR2 (ENSG00000137462), LRRC32 (ENSG00000137507), LRRC3 (ENSG00000160233), LRRC53 (ENSG00000162621), TLR3 (ENSG00000164342), VASN (ENSG00000168140), RXFP1 (ENSG00000171509), NRROS (ENSG00000174004), TLR10 (ENSG00000174123), TLR1 (ENSG00000174125), LRRC3B (ENSG00000179796), TSKU (ENSG00000182704), TLR5 (ENSG00000187554), TLR7 (ENSG00000196664), LRIT2 (ENSG00000204033), LRRC3C (ENSG00000204913)

Protein

Protein identifiers

Toll-like receptor 6 — Q9Y2C9 (reviewed: Q9Y2C9)

All UniProt accessions (2): D6RAV7, Q9Y2C9

UniProt curated annotations — full annotation on UniProt →

Function. Participates in the innate immune response to Gram-positive bacteria and fungi. Specifically recognizes diacylated and, to a lesser extent, triacylated lipopeptides. In response to diacylated lipopeptides, forms the activation cluster TLR2:TLR6:CD14:CD36, this cluster triggers signaling from the cell surface and subsequently is targeted to the Golgi in a lipid-raft dependent pathway. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. Recognizes mycoplasmal macrophage-activating lipopeptide-2kD (MALP-2), soluble tuberculosis factor (STF), phenol-soluble modulin (PSM) and B.burgdorferi outer surface protein A lipoprotein (OspA-L) cooperatively with TLR2. In complex with TLR4, promotes sterile inflammation in monocytes/macrophages in response to oxidized low-density lipoprotein (oxLDL) or amyloid-beta 42. In this context, the initial signal is provided by oxLDL- or amyloid-beta 42-binding to CD36. This event induces the formation of a heterodimer of TLR4 and TLR6, which is rapidly internalized and triggers inflammatory response, leading to the NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion.

Subunit / interactions. Homodimer (via cytoplasmic TIR domain). Heterodimer with TLR2 via their respective extracellular domains. Binds MYD88 via their respective TIR domains. Interacts with CD36, following CD36 stimulation by oxLDL or amyloid-beta 42, and forms a heterodimer with TLR4. The trimeric complex is internalized and triggers inflammatory response. LYN kinase activity facilitates TLR4:TLR6 heterodimerization and signal initiation. The heterodimer TLR2:TLR6 interacts with CD14 and CD36 in response to triacylated lipopeptides.

Subcellular location. Cell membrane. Cytoplasmic vesicle. Phagosome membrane. Membrane raft. Golgi apparatus.

Tissue specificity. Detected in monocytes, CD11c+ immature dendritic cells, plasmacytoid pre-dendritic cells and dermal microvessel endothelial cells.

Similarity. Belongs to the Toll-like receptor family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y2C9-1	1	yes
Q9Y2C9-2	2

RefSeq proteins (2): NP_001381482, NP_006059* (*=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
IPR017241	Toll-like_receptor	Family
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR035897	Toll_tir_struct_dom_sf	Homologous_superfamily

Pfam: PF01463, PF01582, PF13855

UniProt features (77 total): repeat 19, sequence variant 19, helix 11, glycosylation site 9, disulfide bond 4, strand 4, mutagenesis site 3, topological domain 2, domain 2, signal peptide 1, chain 1, transmembrane region 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4OM7	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y2C9-F1	85.76	0.51

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 (4): 117–139, 235–265, 348–373, 424–447

Glycosylation sites (9): 144, 186, 214, 253, 285, 359, 423, 434, 583

Mutagenesis-validated functional residues (3):

Position	Phenotype
678	does not inhibit homodimer formation.
712	inhibits homodimer formation.
716	inhibits homodimer formation.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1236974	ER-Phagosome pathway
R-HSA-166058	MyD88:MAL(TIRAP) cascade initiated on plasma membrane
R-HSA-168188	Toll Like Receptor TLR6:TLR2 Cascade
R-HSA-5602498	MyD88 deficiency (TLR2/4)
R-HSA-5603041	IRAK4 deficiency (TLR2/4)
R-HSA-5686938	Regulation of TLR by endogenous ligand
R-HSA-9833110	RSV-host interactions

MSigDB gene sets: 370 (showing top): GOBP_CELLULAR_RESPONSE_TO_LIPOPROTEIN_PARTICLE_STIMULUS, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_MACROPHAGE_ACTIVATION, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, FISCHER_G1_S_CELL_CYCLE, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_POSITIVE_REGULATION_OF_REACTIVE_OXYGEN_SPECIES_BIOSYNTHETIC_PROCESS, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_ACTIVATION_OF_NF_KAPPAB_INDUCING_KINASE_ACTIVITY

GO Biological Process (33): microglial cell activation (GO:0001774), toll-like receptor signaling pathway (GO:0002224), MyD88-dependent toll-like receptor signaling pathway (GO:0002755), inflammatory response (GO:0006954), immune response (GO:0006955), signal transduction (GO:0007165), activation of NF-kappaB-inducing kinase activity (GO:0007250), positive regulation of gene expression (GO:0010628), negative regulation of interleukin-8 production (GO:0032717), negative regulation of tumor necrosis factor production (GO:0032720), positive regulation of interleukin-1 beta production (GO:0032731), positive regulation of interleukin-6 production (GO:0032755), negative regulation of toll-like receptor 2 signaling pathway (GO:0034136), TRIF-dependent toll-like receptor signaling pathway (GO:0035666), toll-like receptor TLR6:TLR2 signaling pathway (GO:0038124), detection of diacyl bacterial lipopeptide (GO:0042496), defense response to bacterium (GO:0042742), positive regulation of macrophage activation (GO:0043032), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), positive regulation of JUN kinase activity (GO:0043507), innate immune response (GO:0045087), positive regulation of nitric oxide biosynthetic process (GO:0045429), nitric oxide metabolic process (GO:0046209), positive regulation of inflammatory response (GO:0050729), cellular response to diacyl bacterial lipopeptide (GO:0071726), cellular response to oxidised low-density lipoprotein particle stimulus (GO:0140052), positive regulation of cytokine production involved in inflammatory response (GO:1900017), positive regulation of NLRP3 inflammasome complex assembly (GO:1900227), positive regulation of reactive oxygen species biosynthetic process (GO:1903428), cellular response to amyloid-beta (GO:1904646), positive regulation of extrinsic apoptotic signaling pathway (GO:2001238), immune system process (GO:0002376), response to bacterial lipoprotein (GO:0032493)

GO Molecular Function (11): amyloid-beta binding (GO:0001540), transmembrane signaling receptor activity (GO:0004888), signaling receptor binding (GO:0005102), Toll-like receptor 2 binding (GO:0035663), signaling receptor activity (GO:0038023), diacyl lipopeptide binding (GO:0042498), identical protein binding (GO:0042802), protein heterodimerization activity (GO:0046982), lipopeptide binding (GO:0071723), protein binding (GO:0005515), NAD+ nucleosidase activity, cyclic ADP-ribose generating (GO:0061809)

GO Cellular Component (8): Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), phagocytic vesicle membrane (GO:0030670), Toll-like receptor 2-Toll-like receptor 6 protein complex (GO:0035355), signaling receptor complex (GO:0043235), membrane raft (GO:0045121), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-8 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
Toll Like Receptor 2 (TLR2) Cascade	1
Toll-like Receptor Cascades	1
Respiratory Syncytial Virus Infection Pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
macrophage activation	2
toll-like receptor signaling pathway	2
defense response	2
protein binding	2
cytoplasm	2
leukocyte activation involved in inflammatory response	1
glial cell activation	1
pattern recognition receptor signaling pathway	1
immune system process	1
response to stimulus	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
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
negative regulation of cytokine production	1
interleukin-8 production	1
regulation of interleukin-8 production	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
negative regulation of tumor necrosis factor superfamily cytokine production	1
interleukin-1 beta production	1
regulation of interleukin-1 beta production	1
positive regulation of interleukin-1 production	1
positive regulation of cytokine production	1
interleukin-6 production	1
regulation of interleukin-6 production	1
negative regulation of immune system process	1
negative regulation of signal transduction	1
toll-like receptor 2 signaling pathway	1
regulation of toll-like receptor 2 signaling pathway	1
MyD88-independent toll-like receptor signaling pathway	1
detection of bacterial lipopeptide	1
response to diacyl bacterial lipopeptide	1
response to bacterium	1

Protein interactions and networks

STRING

1907 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TLR6	SCARB1	Q8WTV0	993
TLR6	SCARB2	Q14108	993
TLR6	CD36	P16671	993
TLR6	TLR4	O00206	990
TLR6	TLR2	O60603	986
TLR6	TLR1	Q15399	982
TLR6	TIRAP	P58753	976
TLR6	MYD88	P78397	946
TLR6	TLR10	Q9BXR5	929
TLR6	FSTL1	Q12841	916
TLR6	IL6	P05231	856
TLR6	CLEC7A	Q9BXN2	840
TLR6	TLR5	O60602	832
TLR6	IL10	P22301	740
TLR6	IRAK1	P51617	734

IntAct

24 interactions, top by confidence:

A	B	Type	Score
TLR2	TLR6	psi-mi:“MI:0915”(physical association)	0.680
TLR6	TLR2	psi-mi:“MI:0915”(physical association)	0.680
SCGB1D1	MANBA	psi-mi:“MI:0914”(association)	0.640
TLR6	TLR6	psi-mi:“MI:0915”(physical association)	0.580
TLR1	TLR6	psi-mi:“MI:0915”(physical association)	0.550
TLR6	TLR1	psi-mi:“MI:0915”(physical association)	0.550
IQUB	BTBD1	psi-mi:“MI:0914”(association)	0.530
TLR6	TLR4	psi-mi:“MI:0915”(physical association)	0.500
Cd36	TLR4	psi-mi:“MI:0403”(colocalization)	0.430
TLR4	Cd36	psi-mi:“MI:0914”(association)	0.430
SIGLEC5	TLR6	psi-mi:“MI:0915”(physical association)	0.400
TLR6	TLR10	psi-mi:“MI:0915”(physical association)	0.370
CD36	TLR4	psi-mi:“MI:0914”(association)	0.350
TLR1	PLXNB2	psi-mi:“MI:0914”(association)	0.350
TLR2	HMGB1	psi-mi:“MI:0914”(association)	0.350
BMI1	HMGB1P1	psi-mi:“MI:0914”(association)	0.350
TLR1	LRP6	psi-mi:“MI:0914”(association)	0.350
UPK2	IFT56	psi-mi:“MI:0914”(association)	0.350

BioGRID (9): TLR6 (Affinity Capture-MS), TLR6 (Affinity Capture-MS), TLR6 (Reconstituted Complex), TLR6 (Proximity Label-MS), TLR6 (Affinity Capture-MS), TLR6 (Affinity Capture-MS), TLR6 (Affinity Capture-MS), TLR6 (Affinity Capture-RNA), TLR6 (Two-hybrid)

ESM2 similar proteins: A2AIR5, A5D7I4, A8MXE2, A9X1C8, B4F753, B9EKX1, O60242, O60656, O75077, O77485, O77486, O77487, O95803, P16442, P23945, P25291, P97464, Q10981, Q14246, Q16394, Q4R766, Q5GJ04, Q5IGR7, Q5IGR8, Q5M7U7, Q5RBC3, Q5VYY2, Q62452, Q64633, Q64634, Q6AYT7, Q6ZQM8, Q704V6, Q7ZTV5, Q80ZF8, Q8TCU5, Q99LR1, Q9D4Y8, Q9D806, Q9DGB6

Diamond homologs: B2LT61, B2LT62, B2LT64, B2LT65, B3Y613, B3Y614, B3Y615, B3Y618, B5T267, O00206, O60603, P0DUE1, P10810, P34595, P58727, Q0GC71, Q0ZUL9, Q13478, Q15399, Q28680, Q2PZH4, Q2V897, Q2V898, Q61098, Q63691, Q689D1, Q68Y56, Q6GV17, Q6R5N8, Q6T752, Q704V6, Q8SPE8, Q8SPE9, Q95LA9, Q95M53, Q9BXR5, Q9DD78, Q9DGB6, Q9EPQ1, Q9EPW9

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 18 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
MyD88 deficiency (TLR2/4)	5	273.2×	2e-10
IRAK4 deficiency (TLR2/4)	5	259.6×	2e-10
Regulation of TLR by endogenous ligand	5	225.7×	3e-10
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	5	69.2×	1e-07
ER-Phagosome pathway	5	59.0×	2e-07

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of interleukin-6 production	5	55.6×	3e-06
positive regulation of tumor necrosis factor production	5	51.1×	3e-06
inflammatory response	6	15.1×	4e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	81
Likely benign	4
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

345 predictions. Top by Δscore:

Variant	Effect	Δscore
4:38856511:T:TA	donor_gain	0.9800
4:38856520:A:AC	donor_gain	0.9800
4:38856759:A:AC	donor_gain	0.9700
4:38856760:C:CC	donor_gain	0.9700
4:38844268:C:CT	acceptor_gain	0.9600
4:38844265:A:C	acceptor_gain	0.9500
4:38856755:ACT:A	donor_loss	0.9500
4:38856757:TTAC:T	donor_loss	0.9500
4:38856758:T:TC	donor_loss	0.9500
4:38844263:T:C	acceptor_gain	0.9300
4:38829538:C:CC	acceptor_gain	0.9200
4:38856758:TA:T	donor_gain	0.9200
4:38844263:T:TC	acceptor_gain	0.9100
4:38856757:TTA:T	donor_gain	0.9100
4:38856759:A:C	donor_gain	0.9100
4:38829536:TT:T	acceptor_gain	0.9000
4:38856752:TCTAC:T	donor_gain	0.9000
4:38856753:CTACT:C	donor_gain	0.8900
4:38856754:TACTT:T	donor_gain	0.8900
4:38856755:AC:A	donor_gain	0.8900
4:38856756:CT:C	donor_gain	0.8900
4:38856760:CCAAG:C	donor_gain	0.8900
4:38856760:CCA:C	donor_gain	0.8800
4:38856547:T:C	donor_gain	0.8700
4:38856751:TTCTA:T	donor_gain	0.8700
4:38827348:CT:C	donor_gain	0.8600
4:38856759:AC:A	donor_gain	0.8600
4:38856760:CC:C	donor_gain	0.8600
4:38828135:ATCT:A	acceptor_gain	0.8500
4:38830569:G:C	donor_gain	0.8500

AlphaMissense

996 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:38829144:A:C	N110K	0.966
4:38829144:A:T	N110K	0.966
4:38829091:A:G	L128P	0.963
4:38829081:A:C	N131K	0.960
4:38829081:A:T	N131K	0.960
4:38829139:A:G	L112S	0.958
4:38829216:G:C	N86K	0.952
4:38829216:G:T	N86K	0.952
4:38829169:A:G	L102S	0.947
4:38829232:A:G	L81S	0.940
4:38829241:A:G	L78S	0.939
4:38829145:T:A	N110I	0.935
4:38829288:G:C	N62K	0.931
4:38829288:G:T	N62K	0.931
4:38829082:T:A	N131I	0.930
4:38829084:G:C	F130L	0.930
4:38829084:G:T	F130L	0.930
4:38829086:A:G	F130L	0.930
4:38829217:T:A	N86I	0.930
4:38829218:T:A	N86Y	0.930
4:38829146:T:A	N110Y	0.929
4:38829160:A:G	L105S	0.929
4:38829097:A:G	L126S	0.925
4:38829083:T:A	N131Y	0.913
4:38829211:A:G	I88T	0.911
4:38829093:A:C	D127E	0.910
4:38829093:A:T	D127E	0.910
4:38829226:A:G	L83P	0.908
4:38829095:C:G	D127H	0.905
4:38829151:G:A	S108F	0.900

dbSNP variants (sampled 300 via entrez): RS1000009767 (4:38863791 G>A,C), RS1000057825 (4:38864923 T>C), RS1000079449 (4:38825133 G>A), RS1000136098 (4:38857494 G>T), RS1000163531 (4:38835522 T>C), RS1000167090 (4:38857259 G>A,T), RS10002186 (4:38839977 G>C), RS1000262976 (4:38824940 G>A), RS1000293700 (4:38826046 C>A,T), RS1000295310 (4:38857837 T>C), RS1000323112 (4:38864531 C>T), RS1000344500 (4:38849138 A>G), RS1000463574 (4:38852144 T>C), RS1000470988 (4:38858613 G>A), RS1000479057 (4:38841122 T>A)

Disease associations

OMIM: gene MIM:605403 | disease phenotypes: MIM:609888

GenCC curated gene-disease

Mondo (1): leprosy, susceptibility to, 1 (MONDO:0012358)

Orphanet (1): Leprosy (Orphanet:548)

HPO phenotypes

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

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST002014_1	Helicobacter pylori serologic status	1.000000e-18
GCST002083_15	Self-reported allergy	5.000000e-21
GCST002084_3	Allergic sensitization	5.000000e-11
GCST003797_3	Diabetes in response to antihypertensive drug treatment (treatment strategy interaction)	1.000000e-07
GCST003990_4	Allergy	1.000000e-15
GCST006408_2	Allergic sensitization	2.000000e-13
GCST007563_3	Allergic disease (asthma, hay fever or eczema)	1.000000e-16
GCST007563_4	Allergic disease (asthma, hay fever or eczema)	7.000000e-20
GCST007564_38	Asthma or allergic disease (pleiotropy)	2.000000e-19
GCST007994_24	Asthma (age of onset)	5.000000e-22
GCST007995_17	Asthma (childhood onset)	3.000000e-32
GCST009798_22	Asthma	4.000000e-17

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0005298	allergic sensitization measurement
EFO:0005405	response to antihypertensive drug
EFO:0007766	response to beta blocker
EFO:0007767	response to calcium channel blocker

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3259477 (SINGLE PROTEIN), CHEMBL3301399 (PROTEIN COMPLEX)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: catalytic receptor — Toll-like receptor family

ChEMBL bioactivities

13 potent at pChembl≥5 of 15 total, top 13 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.52	EC50	0.3	nM	CHEMBL2179400
9.40	EC50	0.4	nM	CHEMBL5195703
9.10	EC50	0.8	nM	CHEMBL5206630
9.00	EC50	1	nM	CHEMBL5172445
8.30	EC50	5	nM	CHEMBL5178934
7.71	EC50	19.3	nM	CHEMBL2179399
6.87	EC50	133.7	nM	CHEMBL5192180
6.60	EC50	251.8	nM	CHEMBL5203798
5.37	EC50	4269	nM	CHEMBL5207928
5.25	EC50	5636	nM	CHEMBL5196081
5.25	IC50	5600	nM	CHEMBL3935646
5.24	IC50	5700	nM	CHEMBL1313485
5.23	EC50	5866	nM	CHEMBL5189797

PubChem BioAssay actives

13 with measured affinity, of 60 total; 13 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
(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2R)-2-amino-3-[(2R)-2,3-di(hexadecanoyloxy)propyl]sulfanylpropanoyl]amino]-3-hydroxypropanoyl]amino]hexanoyl]amino]hexanoyl]amino]hexanoyl]amino]hexanoic acid	1850733: Agonist activity at human TLR2/TLR6 expressed in HEK-Blue hTLR2-TLR6 cells by SEAP reporter gene based Quanti-blue assay	ec50	0.0003	uM
[(2R)-3-[(2R)-2-amino-3-[[(2S)-3-hydroxy-1-methoxy-1-oxopropan-2-yl]amino]-3-oxopropyl]sulfanyl-2-hexadecanoyloxypropyl] hexadecanoate;hydrochloride	1850733: Agonist activity at human TLR2/TLR6 expressed in HEK-Blue hTLR2-TLR6 cells by SEAP reporter gene based Quanti-blue assay	ec50	0.0004	uM
[(2R)-3-[(2R)-2-acetamido-3-[[(2S)-3-hydroxy-1-methoxy-1-oxopropan-2-yl]amino]-3-oxopropyl]sulfanyl-2-hexadecanoyloxypropyl] hexadecanoate	1850733: Agonist activity at human TLR2/TLR6 expressed in HEK-Blue hTLR2-TLR6 cells by SEAP reporter gene based Quanti-blue assay	ec50	0.0008	uM
[3-[(2R)-2-amino-3-[[(2S)-3-hydroxy-1-methoxy-1-oxopropan-2-yl]amino]-3-oxopropyl]sulfanyl-2-hexadecanoyloxypropyl] hexadecanoate;hydrochloride	1850733: Agonist activity at human TLR2/TLR6 expressed in HEK-Blue hTLR2-TLR6 cells by SEAP reporter gene based Quanti-blue assay	ec50	0.0010	uM
[3-[(2R)-2-acetamido-3-[[(2S)-3-hydroxy-1-methoxy-1-oxopropan-2-yl]amino]-3-oxopropyl]sulfanyl-2-hexadecanoyloxypropyl] hexadecanoate	1850733: Agonist activity at human TLR2/TLR6 expressed in HEK-Blue hTLR2-TLR6 cells by SEAP reporter gene based Quanti-blue assay	ec50	0.0050	uM
(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2R)-3-[(2R)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-2-(hexadecanoylamino)propanoyl]amino]-3-hydroxypropanoyl]amino]hexanoyl]amino]hexanoyl]amino]hexanoyl]amino]hexanoic acid	1850733: Agonist activity at human TLR2/TLR6 expressed in HEK-Blue hTLR2-TLR6 cells by SEAP reporter gene based Quanti-blue assay	ec50	0.0193	uM
[(2S)-3-[(2R)-2-amino-3-[[(2S)-3-hydroxy-1-methoxy-1-oxopropan-2-yl]amino]-3-oxopropyl]sulfanyl-2-hexadecanoyloxypropyl] hexadecanoate;hydrochloride	1850733: Agonist activity at human TLR2/TLR6 expressed in HEK-Blue hTLR2-TLR6 cells by SEAP reporter gene based Quanti-blue assay	ec50	0.1337	uM
[(2S)-3-[(2R)-2-acetamido-3-[[(2S)-3-hydroxy-1-methoxy-1-oxopropan-2-yl]amino]-3-oxopropyl]sulfanyl-2-hexadecanoyloxypropyl] hexadecanoate	1850733: Agonist activity at human TLR2/TLR6 expressed in HEK-Blue hTLR2-TLR6 cells by SEAP reporter gene based Quanti-blue assay	ec50	0.2518	uM
[(2S)-2-hexadecanoyloxy-3-[(2R)-3-[[(2S)-1-methoxy-3-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]amino]-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-oxopropyl]sulfanylpropyl] hexadecanoate	1850733: Agonist activity at human TLR2/TLR6 expressed in HEK-Blue hTLR2-TLR6 cells by SEAP reporter gene based Quanti-blue assay	ec50	4.2690	uM
hexyl 3,4,6-trihydroxy-2-methoxy-5-oxobenzo[7]annulene-8-carboxylate	1989282: Antagonist activity at human TLR2/TLR6	ic50	5.6000	uM
[2-hexadecanoyloxy-3-[(2R)-3-[[(2S)-1-methoxy-3-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]amino]-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-oxopropyl]sulfanylpropyl] hexadecanoate	1850733: Agonist activity at human TLR2/TLR6 expressed in HEK-Blue hTLR2-TLR6 cells by SEAP reporter gene based Quanti-blue assay	ec50	5.6360	uM
ethyl 5-[2-oxo-2-(2,3,4-trihydroxyphenyl)ethyl]furan-2-carboxylate	1989282: Antagonist activity at human TLR2/TLR6	ic50	5.7000	uM
[(2R)-2-hexadecanoyloxy-3-[(2R)-3-[[(2S)-1-methoxy-3-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]amino]-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-oxopropyl]sulfanylpropyl] hexadecanoate	1850733: Agonist activity at human TLR2/TLR6 expressed in HEK-Blue hTLR2-TLR6 cells by SEAP reporter gene based Quanti-blue assay	ec50	5.8660	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sulforaphane	increases expression	2
sodium arsenite	increases expression	2
Tobacco Smoke Pollution	increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
sotorasib	decreases expression, affects cotreatment	1
parthenolide	decreases expression	1
2-anisidine	decreases expression	1
methyleugenol	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
titanium dioxide	increases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	decreases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	decreases expression	1
perfluorooctanoic acid	decreases expression	1
ceric oxide	decreases expression	1
zinc sulfide	affects cotreatment, increases expression	1
cadmium selenide	affects cotreatment, increases expression	1
polyhexamethyleneguanidine	affects reaction, increases expression, increases phosphorylation	1
cobalt oxide	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
lipopolysaccharide, E. coli O26-B6	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
trametinib	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Air Pollutants, Occupational	decreases expression	1
Arsenic	increases expression	1
Benzene	decreases expression	1
Benzo(a)pyrene	increases expression	1

ChEMBL screening assays

28 unique, capped per target: 28 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4429325	Binding	Agonist activity at wild-type human TLR6 expressed in HEK293 cells up to 25 uM measured after 6 hrs by NF-kappaB luciferase reporter gene assay	Novel Pyrimidine Toll-like Receptor 7 and 8 Dual Agonists to Treat Hepatitis B Virus. — J Med Chem

Cellosaurus cell lines

7 cell lines: 5 transformed cell line, 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8R0	Abcam HCT 116 TLR6 KO	Cancer cell line	Male
CVCL_B9TE	Abcam A-549 TLR6 KO	Cancer cell line	Male
CVCL_UF27	HEK-Blue hTLR2 KO-TLR1/6	Transformed cell line	Female
CVCL_UF28	HEK-Blue hTLR2-TLR1	Transformed cell line	Female
CVCL_UF29	HEK-Blue hTLR2-TLR6	Transformed cell line	Female
CVCL_Y390	293/hTLR2-TLR6	Transformed cell line	Female
CVCL_Y399	293/hTLR6-HA	Transformed cell line	Female

Clinical trials (associated diseases)

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