TLR5

Summary

TLR5 (toll like receptor 5, HGNC:11851) is a protein-coding gene on chromosome 1q41, encoding Toll-like receptor 5 (O60602). Pattern recognition receptor (PRR) located on the cell surface that participates in the activation of innate immunity and inflammatory response.

This gene encodes a member of the toll-like receptor (TLR) family, which plays a fundamental role in pathogen recognition and activation of innate immune responses. These receptors recognize distinct pathogen-associated molecular patterns that are expressed on infectious agents. The protein encoded by this gene recognizes bacterial flagellin, the principal component of bacterial flagella and a virulence factor. The activation of this receptor mobilizes the nuclear factor NF-kappaB, which in turn activates a host of inflammatory-related target genes. Mutations in this gene have been associated with both resistance and susceptibility to systemic lupus erythematosus, and susceptibility to Legionnaire disease.

Source: NCBI Gene 7100 — RefSeq curated summary.

At a glance

• Gene–disease (curated): systemic lupus erythematosus, susceptibility to, 1 (Limited, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 132 total — 1 pathogenic, 1 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_003268

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11851
Approved symbol	TLR5
Name	toll like receptor 5
Location	1q41
Locus type	gene with protein product
Status	Approved
Aliases	TIL3, FLJ10052, MGC126430, MGC126431
Ensembl gene	ENSG00000187554
Ensembl biotype	protein_coding
OMIM	603031
Entrez	7100

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 20 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000407096, ENST00000465726, ENST00000484766, ENST00000642471, ENST00000642603, ENST00000645434, ENST00000646044, ENST00000714229, ENST00000860817, ENST00000860818, ENST00000860819, ENST00000860820, ENST00000860821, ENST00000860822, ENST00000860823, ENST00000911266, ENST00000964751, ENST00000964752, ENST00000964753, ENST00000964754, ENST00000964755, ENST00000964756, ENST00000964757

RefSeq mRNA: 1 — MANE Select: NM_003268 NM_003268

CCDS: CCDS31033

Canonical transcript exons

ENST00000642603 — 6 exons

Exon	Start	End
ENSE00001377361	223134682	223134864
ENSE00001382825	223132475	223132639
ENSE00001442884	223137178	223137263
ENSE00001553087	223109404	223113035
ENSE00001909027	223143196	223143248
ENSE00002203038	223141648	223141763

Expression profiles

Bgee: expression breadth ubiquitous, 243 present calls, max score 90.66.

FANTOM5 (CAGE): breadth broad, TPM avg 1.3094 / max 62.3059, expressed in 460 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
17625	1.0276	389
17626	0.2573	130
17624	0.0245	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	90.66	gold quality
mononuclear cell	CL:0000842	90.49	gold quality
leukocyte	CL:0000738	90.06	gold quality
blood	UBERON:0000178	86.73	gold quality
epithelium of bronchus	UBERON:0002031	84.34	gold quality
left ovary	UBERON:0002119	84.11	gold quality
bronchial epithelial cell	CL:0002328	83.89	gold quality
bronchus	UBERON:0002185	83.83	gold quality
right ovary	UBERON:0002118	83.73	gold quality
epithelium of mammary gland	UBERON:0003244	82.99	gold quality
mammary duct	UBERON:0001765	82.74	gold quality
lower lobe of lung	UBERON:0008949	82.61	gold quality
ovary	UBERON:0000992	81.78	gold quality
mucosa of paranasal sinus	UBERON:0005030	81.59	gold quality
granulocyte	CL:0000094	81.26	gold quality
minor salivary gland	UBERON:0001830	80.59	gold quality
saliva-secreting gland	UBERON:0001044	80.55	gold quality
esophagus squamous epithelium	UBERON:0006920	80.07	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.00	gold quality
secondary oocyte	CL:0000655	79.44	gold quality
mouth mucosa	UBERON:0003729	79.31	gold quality
hair follicle	UBERON:0002073	79.19	silver quality
epithelium of nasopharynx	UBERON:0001951	78.68	gold quality
esophagus mucosa	UBERON:0002469	78.63	gold quality
gall bladder	UBERON:0002110	78.52	gold quality
cervix squamous epithelium	UBERON:0006922	78.01	silver quality
epithelium of esophagus	UBERON:0001976	77.48	gold quality
sperm	CL:0000019	77.34	silver quality
oral cavity	UBERON:0000167	77.31	gold quality
mammary gland	UBERON:0001911	77.27	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.05

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
IL6	Activation

Upstream regulators (CollecTRI, top): GATA3, RELA

miRNA regulators (miRDB)

55 targeting TLR5, 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-1252-5P	100.00	69.80	2774
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-7159-3P	99.51	70.17	1920
HSA-MIR-409-3P	99.50	66.33	1192
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-19A-5P	99.36	66.93	1675

Literature-anchored findings (GeneRIF, showing 40)

• Gram-negative flagellin-induced self-tolerance is associated with a block in interleukin-1 receptor-associated kinase release from toll-like receptor 5. (PMID:11953430)
• role of two nonadjacent regions in enteroaggregative Escherichia coli flagellin are required for activation (PMID:12185085)
• All nine patients expressed all of the TLRs studied, whereas only five out of the nine patients had any granulomas positive for IL-4.The associations between TLRs 1, 5, and 9 were different in IL-4-negative compared with IL-4-positive patients. (PMID:12600829)
• results indicate that epithelial TLR5 mediates p38 activation and subsequently regulates flagellin-induced IL-8 expression independently of NF-kappaB, probably by influencing IL-8 mRNA translation (PMID:12702497)
• By their surface expression of TLR5 and sensitivity to bacterial flagellin stimulation, with concomitant chemokine and cytokine production, dendritic cells provide a mechanism by which motile bacteria can initiate an acquired immune response. (PMID:12734364)
• TLR5 may represent an important mechanism underlying the recognition of bacterial pathogens by osteoblasts during bone infections. (PMID:12933896)
• Data show that flagella signaling in airway cells can be initiated by interactions with asialoGM1 and toll-like receptor (TLR)2 as well as by activation of TLR5. (PMID:14607814)
• TLR5 has a role in promotion of hBD-2 expression via mitogen-activated protein kinase along with gangliosides and Salmonella FliC protein (PMID:14707135)
• Microvascular endothelial cells, representing the barrier between circulating immune cells and the intestinal mucosa, functionally express TLR5, which plays a previously unrecognized role in the innate immune response toward bacterial antigens. (PMID:15067088)
• in non-transformed human colonocytes, MEK activation following flagellin/TLR5 engagement is a key modulator for NFkappaB-independent, IL-8 and MIP3alpha expression. (PMID:15069060)
• identification of two common single nucleotide polymorphisms (PMID:15135456)
• TLR5 is activated in intestinal epithelial cells by a commensal Escherichia coli strain (PMID:15302888)
• The memory B-cell subset expressed higher densities of TLR9 as compared with naive B cells in primary biliaary cirrhosis. (PMID:15685542)
• Helicobacter pylori induces interleukin-8 secretion by Toll-like receptor 2- and Toll-like receptor 5-dependent and -independent pathways (PMID:15731050)
• Toll-like receptor 5 has a role in survival of flagellated bacteria (PMID:15956202)
• A stop codon polymorphism of Toll-like receptor 5 is associated with resistance to systemic lupus erythematosus. (PMID:16027372)
• first study describing TLR expression on tumor cells of gastric carcinoma and its precursor lesions (PMID:16044857)
• The interaction of TLR5 with S. typhimurium fliC in the initiation of the inflammatory and apoptotic response of gastrointestinal epithelial cells is reported. (PMID:16179598)
• the airway epithelial receptor TLR5 senses P. aeruginosa through its flagellin protein, which may have an important role in the initiation of the host inflammatory reaction to clear the invading pathogen (PMID:16239509)
• Costimulation of effector T cells with anti-CD3 and TLR5 ligand flagellin resulted in enhanced proliferation and production of IL-2, and potently increased their suppressive capacity and enhanced expression of FOXP3. (PMID:16339542)
• These results demonstrate that natural acquisition of immune responses to flagellin are regulated by TLR5 and suggest that immune responses to flagellin are not merely associated with CD but rather promote the pathogenic response. (PMID:16439468)
• analysis of single nucleotide polymorphisms in the human TLR5 gene (PMID:16470719)
• MyD88 bridges TLR5 engagement to PI3K activation in response to flagellin (PMID:16644730)
• TLR5’s rapid activation of phosphoinositide 3-kinase serves to limit MAP kinase signaling, thus limiting proinflammatory gene expression and reducing the potential negative consequences of proinflammatory gene expression. (PMID:16670329)
• These data suggest a critical role of NOD2/CARD15 in the bacterial clearance of the intestinal epithelium while Crohn’s disease (CD)-specific mutated NOD2/CARD15 causes an impaired epithelial barrier. (PMID:16897777)
• A conserved surface on Toll-like receptor 5 recognizes bacterial flagellin. (PMID:17283206)
• Phosphorylation of TLR5 by PKD may be one of the proximal elements in the cellular response to flagellin, and that this event contributes to p38 MAPK activation and production of inflammatory cytokines in epithelial cells. (PMID:17442957)
• Our results do not indicate a major influence of these putative functional TLR5 and TLR9 single nucleotide polymorphisms on the susceptibility to (or protection from) systemic lupus erythematosus. (PMID:17516623)
• TLR5 may play a significant role in tumor progression of cervical neoplasia and may represent a useful marker for malignant transformation of cervical squamous cells. (PMID:17587322)
• Microbial patterns signaling via Toll-like receptors 2 and 5 contribute to epithelial repair, growth and survival. This effect is independent of hematopoietic and other cells as well as inflammatory cytokines (PMID:18167552)
• FlaA of V. cholerae could induce IL-1beta expression by recognizing TLR5 that activate NF-kappaB and MAP kinase in Int407 cells. (PMID:18314303)
• study demonstrated that TLR signaling appears to mediate the excessive cytokine production occurring in cystic fibrosis; inhibition of TLR5 abolished the damaging inflammatory response generated by CF airway cells following exposure to P. aeruginosa (PMID:18490781)
• Toll-like receptor 5 engagement modulates tumor development and growth in a mouse xenograft model of human colon cancer. (PMID:18538140)
• mutation at position 1174 in the coding sequence is associated with Legionnaires’ disease and is negatively associated with the occurrence of Crohn’s disease (PMID:18590761)
• TLR5, but neither TLR2 nor TLR4, critically regulated Brukholderia cenocepacia-induced lung epithelial inflammatory response. (PMID:18680520)
• Toll-like receptor (TLR)5 is stored intracellularly in neutrophils and is mobilized to the cell surface in a protein synthesis-independent manner after stimulation with TLR ligands and cytokines characteristic of cystic fibrosis airway microenvironment. (PMID:18684966)
• 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)
• lower expression in asthmatic patients (PMID:19067129)
• polymorphism is associated with susceptibility to pneumonia caused by the flagellated bacterium Legionella pneumophila (PMID:19120490)
• enteropathogenic E. coli can trigger mucosal IL-8 responses by apical flagellin/TLR5 interaction ex vivo and does not require access to the basolateral membrane as postulated in cell culture models. (PMID:19134113)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tlr5	ENSMUSG00000079164
rattus_norvegicus	Tlr5	ENSRNOG00000022067

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), TLR6 (ENSG00000174130), LRRC3B (ENSG00000179796), TSKU (ENSG00000182704), TLR7 (ENSG00000196664), LRIT2 (ENSG00000204033), LRRC3C (ENSG00000204913)

Protein

Protein identifiers

Toll-like receptor 5 — O60602 (reviewed: O60602)

Alternative names: Toll/interleukin-1 receptor-like protein 3

All UniProt accessions (4): A0A2R8Y4Q2, A0A2R8Y7Z4, B1AZ06, O60602

UniProt curated annotations — full annotation on UniProt →

Function. Pattern recognition receptor (PRR) located on the cell surface that participates in the activation of innate immunity and inflammatory response. Recognizes small molecular motifs named pathogen-associated molecular pattern (PAMPs) expressed by pathogens and microbe-associated molecular patterns (MAMPs) usually expressed by resident microbiota. Upon ligand binding such as bacterial flagellins, recruits intracellular adapter proteins MYD88 and TRIF leading to NF-kappa-B activation, cytokine secretion and induction of the inflammatory response. Plays thereby an important role in the relationship between the intestinal epithelium and enteric microbes and contributes to the gut microbiota composition throughout life.

Subunit / interactions. Homodimer. Interacts with MYD88 (via TIR domain). Interacts with TICAM1 (via TIR domain). Interacts with UNC93B1; this interaction is essential for proper TLR5 localization to the plasma membrane.

Subcellular location. Cell membrane.

Tissue specificity. Highly expressed on the basolateral surface of intestinal epithelia. Expressed also in other cells such as lung epithelial cells.

Post-translational modifications. Phosphorylated at Ser-805 by PKD/PRKD1; phosphorylation induces the production of inflammatory cytokines. Phosphorylated at Tyr-798 upon flagellin binding; required for signaling.

Disease relevance. Systemic lupus erythematosus 1 (SLEB1) [MIM:601744] A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Polymorphism. Individuals with a common stop codon polymorphism in position 392 are unable to mediate flagellin signaling. This polymorphism acts in a dominant fashion and is associated with susceptibility to pneumonia caused by Legionella pneumophila [MIM:608556]. It also provides protection against systemic lupus erythematosus. A nonsense TLR5 polymorphism, resulting in p.Arg392Ter, confers resistance to melioidosis [MIM:615557], an infection caused by the Gram-negative, flagellated soil saprophyte Burkholderia pseudomallei. Carriers of this hypofunctional TLR5 variant may generate impaired inflammatory responses during melioidosis infection that result in reduced organ failure and lower mortality.

Similarity. Belongs to the Toll-like receptor family.

RefSeq proteins (1): NP_003259* (*=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: PF00560, PF01582, PF13855

UniProt features (51 total): repeat 20, sequence variant 9, glycosylation site 7, sequence conflict 3, topological domain 2, domain 2, modified residue 2, disulfide bond 2, signal peptide 1, chain 1, transmembrane region 1, helix 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3J0A	ELECTRON MICROSCOPY	26
8AR2	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60602-F1	89.00	0.70

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 (2): 798, 805

Disulfide bonds (2): 583–610, 585–629

Glycosylation sites (7): 37, 46, 245, 342, 422, 595, 598

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-168176	Toll Like Receptor 5 (TLR5) Cascade
R-HSA-5602680	MyD88 deficiency (TLR5)
R-HSA-5603037	IRAK4 deficiency (TLR5)
R-HSA-975871	MyD88 cascade initiated on plasma membrane

MSigDB gene sets: 171 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_POSITIVE_REGULATION_OF_INTERLEUKIN_8_PRODUCTION, GOBP_CELLULAR_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_TOLL_LIKE_RECEPTOR_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_CYTOKINE_PRODUCTION, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, BOYAULT_LIVER_CANCER_SUBCLASS_G1_UP, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS

GO Biological Process (12): toll-like receptor signaling pathway (GO:0002224), inflammatory response (GO:0006954), male gonad development (GO:0008584), positive regulation of interleukin-8 production (GO:0032757), toll-like receptor 5 signaling pathway (GO:0034146), innate immune response (GO:0045087), positive regulation of nitric oxide biosynthetic process (GO:0045429), cellular response to lipopolysaccharide (GO:0071222), cellular response to mechanical stimulus (GO:0071260), immune system process (GO:0002376), immune response (GO:0006955), signal transduction (GO:0007165)

GO Molecular Function (5): transmembrane signaling receptor activity (GO:0004888), interleukin-1 receptor binding (GO:0005149), signaling receptor activity (GO:0038023), pattern recognition receptor activity (GO:0038187), protein binding (GO:0005515)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Diseases associated with the TLR signaling cascade	2
Toll-like Receptor Cascades	1
Toll Like Receptor 10 (TLR10) Cascade	1
Toll Like Receptor 5 (TLR5) Cascade	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signaling receptor activity	2
pattern recognition receptor signaling pathway	1
defense response	1
gonad development	1
development of primary male sexual characteristics	1
positive regulation of cytokine production	1
interleukin-8 production	1
regulation of interleukin-8 production	1
cell surface toll-like receptor signaling pathway	1
immune response	1
defense response to symbiont	1
nitric oxide biosynthetic process	1
positive regulation of biosynthetic process	1
regulation of nitric oxide biosynthetic process	1
response to lipopolysaccharide	1
cellular response to molecule of bacterial origin	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
response to mechanical stimulus	1
cellular response to abiotic stimulus	1
cellular response to external stimulus	1
biological_process	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
cytokine receptor binding	1
growth factor receptor binding	1
molecular transducer activity	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2912 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TLR5	MYD88	P78397	998
TLR5	TIRAP	P58753	935
TLR5	TLR4	O00206	911
TLR5	HMGB1	P09429	896
TLR5	IRAK1	P51617	890
TLR5	LY96	Q9Y6Y9	863
TLR5	NOD2	Q9HC29	841
TLR5	IL1A	P01583	839
TLR5	SIGIRR	Q6IA17	835
TLR5	TLR6	Q9Y2C9	832
TLR5	TLR1	Q15399	828
TLR5	IL1R1	P14778	824
TLR5	IL1B	P01584	820
TLR5	IL6	P05231	817
TLR5	TNF	P01375	817

IntAct

22 interactions, top by confidence:

A	B	Type	Score
TLR5	APP	psi-mi:“MI:0407”(direct interaction)	0.560
APP	TLR5	psi-mi:“MI:0407”(direct interaction)	0.560
ACOT12	INPPL1	psi-mi:“MI:0914”(association)	0.530
TLR5	MAN1A2	psi-mi:“MI:0914”(association)	0.530
CD22	TLR5	psi-mi:“MI:0915”(physical association)	0.400
CD33	TLR5	psi-mi:“MI:0915”(physical association)	0.400
SIGLEC5	TLR5	psi-mi:“MI:0915”(physical association)	0.400
SIGLEC6	TLR5	psi-mi:“MI:0915”(physical association)	0.400
SIGLEC7	TLR5	psi-mi:“MI:0915”(physical association)	0.400
SIGLEC9	TLR5	psi-mi:“MI:0915”(physical association)	0.400
SIGLEC11	TLR5	psi-mi:“MI:0915”(physical association)	0.400
TLR5	APP	psi-mi:“MI:0915”(physical association)	0.400
ZG16B	TLR5	psi-mi:“MI:0915”(physical association)	0.400
TLR5	MYD88	psi-mi:“MI:0915”(physical association)	0.400
TLR5	TLR5	psi-mi:“MI:0915”(physical association)	0.370
CHSY3	TLR5	psi-mi:“MI:0914”(association)	0.350

BioGRID (26): DHRS3 (Affinity Capture-MS), PTRH2 (Affinity Capture-MS), CNPY3 (Affinity Capture-MS), TLR5 (Affinity Capture-MS), SNX14 (Affinity Capture-MS), FAM213A (Affinity Capture-MS), DHRS7 (Affinity Capture-MS), DDRGK1 (Affinity Capture-MS), TMX2 (Affinity Capture-MS), CTDNEP1 (Affinity Capture-MS), MAN1A2 (Affinity Capture-MS), TLR5 (Two-hybrid), TLR5 (Two-hybrid), TLR5 (Affinity Capture-MS), DHRS3 (Affinity Capture-MS)

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: A1KZ92, A2AJ76, A2CG49, A4IGL7, A4IIW9, A8WGA3, A8WHP9, B0BNK7, B1H234, D2HFT7, D3YXG0, D3YYU8, D3ZZ80, D4A1J9, D4ABX8, O01761, O15146, O35930, O42414, O55005, O60229, O60602, O75147, O89026, O97394, P0C5H6, P0C6S8, P0C7J6, P11627, P11799, P15209, P20241, P22648, P32004, P43146, P70211, P97924, P98160, Q05695, Q05793

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PRKD1	up-regulates	TLR5	phosphorylation
TLR5	“up-regulates quantity by expression”	IL6	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 14 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	6	43.6×	2e-07
Adaptive Immune System	7	17.4×	1e-06

GO biological processes:

GO term	Partners	Fold	FDR
cell adhesion	9	24.1×	2e-09

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	97
Likely benign	12
Benign	7

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
979934	GRCh37/hg19 1q41-42.12(chr1:222605125-224696628)x1	Pathogenic
3767955	NM_003268.6(TLR5):c.603dup (p.Ser202Ter)	Likely pathogenic

SpliceAI

592 predictions. Top by Δscore:

Variant	Effect	Δscore
1:223134398:T:TA	donor_gain	0.9900
1:223137174:ATACC:A	donor_loss	0.9800
1:223129211:TCTAC:T	donor_gain	0.9600
1:223135659:G:A	donor_gain	0.9600
1:223113036:C:CC	acceptor_gain	0.9500
1:223132474:CCT:C	donor_gain	0.9400
1:223113034:TC:T	acceptor_gain	0.9300
1:223113035:CC:C	acceptor_gain	0.9300
1:223133249:T:TA	donor_gain	0.9300
1:223113033:ATCCT:A	acceptor_loss	0.9100
1:223113035:CCTAT:C	acceptor_loss	0.9100
1:223113037:T:G	acceptor_loss	0.9100
1:223132468:CACT:C	donor_loss	0.9000
1:223132469:ACTT:A	donor_loss	0.9000
1:223132470:CTTA:C	donor_loss	0.9000
1:223132471:TTA:T	donor_loss	0.9000
1:223132472:TA:T	donor_loss	0.9000
1:223135622:AAAT:A	donor_gain	0.9000
1:223129213:TA:T	donor_gain	0.8900
1:223113031:TGATC:T	acceptor_gain	0.8700
1:223133255:A:C	donor_gain	0.8300
1:223134384:G:C	donor_gain	0.8300
1:223135703:C:CA	donor_gain	0.8200
1:223132636:TTTCC:T	acceptor_loss	0.8100
1:223132637:TTCCT:T	acceptor_loss	0.8100
1:223132638:TCCTA:T	acceptor_loss	0.8100
1:223132641:T:A	acceptor_loss	0.8100
1:223132467:GCACT:G	donor_loss	0.8000
1:223132473:A:AC	donor_gain	0.8000
1:223132474:C:CC	donor_gain	0.8000

AlphaMissense

5708 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:223110755:G:C	S759R	0.990
1:223110755:G:T	S759R	0.990
1:223110757:T:G	S759R	0.990
1:223111295:G:C	N579K	0.988
1:223111295:G:T	N579K	0.988
1:223111440:A:G	L531P	0.988
1:223111434:A:T	L533H	0.986
1:223111297:T:A	N579Y	0.985
1:223111358:G:C	N558K	0.985
1:223111358:G:T	N558K	0.985
1:223111359:T:A	N558I	0.985
1:223111565:C:A	W489C	0.985
1:223111565:C:G	W489C	0.985
1:223110580:A:G	W818R	0.984
1:223110580:A:T	W818R	0.984
1:223111434:A:G	L533P	0.984
1:223111567:A:G	W489R	0.984
1:223111567:A:T	W489R	0.984
1:223111253:C:A	W593C	0.983
1:223111253:C:G	W593C	0.983
1:223111496:G:C	N512K	0.983
1:223111496:G:T	N512K	0.983
1:223110756:C:A	S759I	0.982
1:223111424:G:C	N536K	0.982
1:223111424:G:T	N536K	0.982
1:223111374:A:G	L553P	0.980
1:223111202:A:C	C610W	0.979
1:223111203:C:G	C610S	0.979
1:223111204:A:G	C610R	0.979
1:223111204:A:T	C610S	0.979

dbSNP variants (sampled 300 via entrez): RS1000036023 (1:223145107 C>T), RS1000089772 (1:223129993 C>T), RS1000099772 (1:223139134 C>A), RS1000114738 (1:223136835 T>A,C,G), RS1000168463 (1:223136456 T>C), RS1000173823 (1:223139519 A>C,G), RS1000240065 (1:223111188 G>A,C), RS1000292015 (1:223129673 G>A), RS1000414332 (1:223124383 T>C), RS1000450261 (1:223126313 A>G), RS1000562720 (1:223119306 T>G), RS1000598742 (1:223131559 GTTTGTT>G), RS1000662359 (1:223129962 C>T), RS1000689639 (1:223115526 C>G), RS1000720461 (1:223115695 G>A)

Disease associations

OMIM: gene MIM:603031 | disease phenotypes: MIM:601744, MIM:608556

GenCC curated gene-disease

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
systemic lupus erythematosus, susceptibility to, 1	Limited	UD

Mondo (2): systemic lupus erythematosus, susceptibility to, 1 (MONDO:0011138), legionnaire disease, susceptibility to (MONDO:0012057)

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90002394_98	Monocyte percentage of white cells	1.000000e-13

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007989	monocyte percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2176839 (SINGLE PROTEIN)

PharmGKB: 0 entries

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs5744174	Efficacy	3	ustekinumab	Psoriasis

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs5744174	TLR5	3	3.00	1	ustekinumab
rs5744168	TLR5		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: catalytic receptor — Toll-like receptor family

ChEMBL bioactivities

5 potent at pChembl≥5 of 6 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.07	IC50	850	nM	CHEMBL4795753
5.62	IC50	2400	nM	CHEMBL4795714
5.50	IC50	3130	nM	CHEMBL5423509
5.47	IC50	3380	nM	CHEMBL5436800

PubChem BioAssay actives

5 with measured affinity, of 195 total; 4 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
6-[(4-benzyl-5-pyridin-4-yl-1,2,4-triazol-3-yl)sulfanyl]-8-thia-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaene	1692747: Inhibition of Flagellin-BS binding to human TLR5 expressed in HEK293 cells harboring SEAP reporter gene preincubated for 24 hrs followed by compound wash out and subsequent Flagellin-BS addition along with compound and measured after 0.5 hrs by QUANTI-Blue assay	ic50	0.8500	uM
1-pentyl-4-(2-phenylmethoxyphenyl)imidazol-2-amine;hydrochloride	1734128: Inhibition of human TLR5 stably expressed in HEK293 cells cotransfected with secreted alkaline phosphatase assessed as assessed as inhibition of flagellin-induced NF-kappaB activation by quanti-blue SEAP reporter gene based spectrophotometric method	ic50	2.4000	uM
6-[(4-phenyl-5-pyridin-4-yl-1,2,4-triazol-3-yl)sulfanyl]-8-thia-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaene	1989276: Antagonist activity at TLR5 (unknown origin)	ic50	3.1300	uM
2-pyridin-4-yl-5-(8-thia-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaen-6-ylsulfanyl)-1,3,4-oxadiazole	1989276: Antagonist activity at TLR5 (unknown origin)	ic50	3.3800	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Nickel	decreases expression	3
Tobacco Smoke Pollution	decreases expression	3
Arsenic	increases abundance, increases expression, decreases expression	2
Benzo(a)pyrene	decreases methylation, affects methylation, decreases expression	2
Progesterone	decreases expression, increases expression	2
Smoke	decreases expression, increases abundance	2
Asian ginseng	decreases expression, affects cotreatment	1
parthenolide	decreases expression	1
sodium arsenate	decreases expression, increases abundance	1
trichostatin A	increases expression	1
benzo(e)pyrene	increases methylation	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
Aripiprazole	affects cotreatment, decreases expression, increases expression	1
Resveratrol	affects cotreatment, increases secretion	1
Zoledronic Acid	increases expression	1
Aerosols	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Air Pollutants, Occupational	decreases expression	1
Antigens, Bacterial	increases activity	1
Vehicle Emissions	decreases expression	1
Benzene	increases expression	1
Diethylhexyl Phthalate	affects cotreatment, decreases expression	1
Estradiol	affects cotreatment, decreases expression	1
Metformin	affects cotreatment, increases expression	1
Methapyrilene	increases methylation	1
Ozone	affects cotreatment, decreases expression	1
Silicon Dioxide	decreases expression	1
Valproic Acid	decreases expression	1
Paclitaxel	affects cotreatment, increases expression	1

ChEMBL screening assays

22 unique, capped per target: 21 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2187103	Functional	Agonist activity at human TLR5 expressed in HEK293 cells assessed as induction of NF-kappaB activity by measuring extracellular secreted alkaline phosphatase up to 250 uM by HEK-blue reporter gene assay	Structure-activity relationships in human Toll-like receptor 8-active 2,3-diamino-furo[2,3-c]pyridines. — J Med Chem
CHEMBL2389991	Binding	Activation of human TLR5 transfected in HEK293 cells at 10 uM after 20 to 24 hrs by SEAP assay	Identification of substituted pyrimido[5,4-b]indoles as selective Toll-like receptor 4 ligands. — J Med Chem

Cellosaurus cell lines

17 cell lines: 17 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_5I78	HEK-Blue KD-TLR5	Transformed cell line	Female
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

Clinical trials (associated diseases)

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