TRIL

Summary

TRIL (TLR4 interactor with leucine rich repeats, HGNC:22200) is a protein-coding gene on chromosome 7p14.3, encoding TLR4 interactor with leucine rich repeats (Q7L0X0). Component of the TLR4 signaling complex.

TRIL is a component of the TLR4 (MIM 603030) complex and is induced in a number of cell types by lipopolysaccharide (LPS) (Carpenter et al., 2009 [PubMed 19710467]).

Source: NCBI Gene 9865 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 126 total
• MANE Select transcript: NM_014817

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:22200
Approved symbol	TRIL
Name	TLR4 interactor with leucine rich repeats
Location	7p14.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0644
Ensembl gene	ENSG00000255690
Ensembl biotype	protein_coding
OMIM	613356
Entrez	9865

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000539664

RefSeq mRNA: 1 — MANE Select: NM_014817 NM_014817

CCDS: CCDS75573

Canonical transcript exons

ENST00000539664 — 1 exons

Exon	Start	End
ENSE00002268540	28953358	28958330

Expression profiles

Bgee: expression breadth ubiquitous, 234 present calls, max score 94.71.

FANTOM5 (CAGE): breadth broad, TPM avg 4.1486 / max 141.1581, expressed in 469 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
83379	2.4679	363
83380	1.1390	305
83381	0.3233	150
83382	0.2184	121

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
medial globus pallidus	UBERON:0002477	94.71	gold quality
lateral globus pallidus	UBERON:0002476	94.32	gold quality
globus pallidus	UBERON:0001875	94.02	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	91.48	gold quality
substantia nigra pars compacta	UBERON:0001965	89.85	gold quality
substantia nigra pars reticulata	UBERON:0001966	89.61	gold quality
substantia nigra	UBERON:0002038	89.09	gold quality
caudate nucleus	UBERON:0001873	88.77	gold quality
putamen	UBERON:0001874	88.72	gold quality
midbrain	UBERON:0001891	88.63	gold quality
CA1 field of hippocampus	UBERON:0003881	88.38	gold quality
amygdala	UBERON:0001876	88.25	gold quality
nucleus accumbens	UBERON:0001882	88.14	gold quality
ventral tegmental area	UBERON:0002691	87.61	gold quality
inferior olivary complex	UBERON:0002127	87.08	gold quality
temporal lobe	UBERON:0001871	86.95	gold quality
hypothalamus	UBERON:0001898	86.28	gold quality
entorhinal cortex	UBERON:0002728	86.11	gold quality
superior vestibular nucleus	UBERON:0007227	85.47	gold quality
Ammon’s horn	UBERON:0001954	85.42	gold quality
endothelial cell	CL:0000115	85.33	gold quality
medulla oblongata	UBERON:0001896	84.62	gold quality
cranial nerve II	UBERON:0000941	84.54	gold quality
Brodmann (1909) area 9	UBERON:0013540	84.44	gold quality
subthalamic nucleus	UBERON:0001906	84.23	gold quality
telencephalon	UBERON:0001893	84.17	gold quality
right frontal lobe	UBERON:0002810	84.11	gold quality
dorsal plus ventral thalamus	UBERON:0001897	83.55	gold quality
postcentral gyrus	UBERON:0002581	83.43	gold quality
mammary duct	UBERON:0001765	83.41	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ENAD-20	yes	386.62
E-ANND-3	yes	3.25

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

169 targeting TRIL, 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-4673	100.00	66.64	1490
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627

Literature-anchored findings (GeneRIF, showing 2)

• Toll-like receptor 3 (TLR3) signaling requires TLR4 Interactor with leucine-rich REPeats (TRIL) (PMID:21911501)
• Tril dampens Nodal signaling through Pellino2- and Traf6-mediated activation of Nedd4l. (PMID:34475212)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	tril	ENSDARG00000100791
mus_musculus	Tril	ENSMUSG00000043496
rattus_norvegicus	Tril	ENSRNOG00000026941
drosophila_melanogaster	Con	FBGN0005775
drosophila_melanogaster	kek3	FBGN0028370
drosophila_melanogaster	CG18095	FBGN0028872
drosophila_melanogaster	CG7509	FBGN0035575
caenorhabditis_elegans	lron-9	WBGENE00011971
caenorhabditis_elegans		WBGENE00020649
caenorhabditis_elegans		WBGENE00022789

Paralogs (22): CHADL (ENSG00000100399), LGI1 (ENSG00000108231), LGR6 (ENSG00000133067), CHAD (ENSG00000136457), LRIG3 (ENSG00000139263), LGR5 (ENSG00000139292), LRIG1 (ENSG00000144749), LRRTM2 (ENSG00000146006), LRIT1 (ENSG00000148602), LGI2 (ENSG00000153012), LGI4 (ENSG00000153902), LRRC52 (ENSG00000162763), ELFN2 (ENSG00000166897), LGI3 (ENSG00000168481), LRG1 (ENSG00000171236), CPN2 (ENSG00000178772), LRIT3 (ENSG00000183423), LRRC26 (ENSG00000184709), LRIG2 (ENSG00000198799), LGR4 (ENSG00000205213), ELFN1 (ENSG00000225968), LRRC24 (ENSG00000254402)

Protein

Protein identifiers

TLR4 interactor with leucine rich repeats — Q7L0X0 (reviewed: Q7L0X0)

Alternative names: Leucine-rich repeat-containing protein KIAA0644

All UniProt accessions (1): Q7L0X0

UniProt curated annotations — full annotation on UniProt →

Function. Component of the TLR4 signaling complex. Mediates the innate immune response to bacterial lipopolysaccharide (LPS) leading to cytokine secretion.

Subunit / interactions. Belongs to the lipopolysaccharide (LPS) receptor, a multi-protein complex containing at least CD14, MD-2 and TLR4. Interacts with TLR4; this interaction is greatly enhanced by LPS stimulation. Interacts with LPS.

Subcellular location. Membrane.

Tissue specificity. Highly expressed in the brain, ovary, small intestine and spleen.

Post-translational modifications. N-glycolysaled.

Induction. By bacterial lipopolysaccharides (LPS).

RefSeq proteins (1): NP_055632* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000483	Cys-rich_flank_reg_C	Domain
IPR001611	Leu-rich_rpt	Repeat
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR003961	FN3_dom	Domain
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR050328	Dev_Immune_Receptor	Family

Pfam: PF13855

UniProt features (30 total): repeat 12, sequence variant 4, glycosylation site 3, domain 2, topological domain 2, compositionally biased region 2, signal peptide 1, chain 1, region of interest 1, modified residue 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7L0X0-F1	72.40	0.42

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 (1): 798

Glycosylation sites (3): 73, 209, 589

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 129 (showing top): TAATAAT_MIR126, GOBP_INFLAMMATORY_RESPONSE, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, 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, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_DN, GGCAGTG_MIR3243P, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_CYTOKINE_PRODUCTION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_REGULATION_OF_RESPONSE_TO_BIOTIC_STIMULUS

GO Biological Process (5): regulation of cytokine production involved in immune response (GO:0002718), inflammatory response (GO:0006954), toll-like receptor 4 signaling pathway (GO:0034142), innate immune response (GO:0045087), immune system process (GO:0002376)

GO Molecular Function (3): lipopolysaccharide binding (GO:0001530), signaling receptor activity (GO:0038023), protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), lipopolysaccharide receptor complex (GO:0046696), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of cytokine production	1
cytokine production involved in immune response	1
regulation of production of molecular mediator of immune response	1
defense response	1
cell surface toll-like receptor signaling pathway	1
immune response	1
defense response to symbiont	1
biological_process	1
lipid binding	1
carbohydrate derivative binding	1
molecular transducer activity	1
binding	1
membrane	1
cell periphery	1
signaling receptor complex	1
membrane protein complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1026 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRIL	TRIR	Q9BQ61	706
TRIL	FN1	P02751	457
TRIL	TLR4	O00206	453
TRIL	SLC25A35	Q3KQZ1	430
TRIL	TRAF3IP3	Q9Y228	422
TRIL	RYBP	Q8N488	391
TRIL	NRDC	O43847	383
TRIL	VTCN1	Q7Z7D3	318
TRIL	HMGXB4	Q9UGU5	305
TRIL	CNPY3	Q9BT09	305
TRIL	ZNF286A	Q9HBT8	295
TRIL	ZBTB39	O15060	292
TRIL	IL22RA2	Q969J5	289
TRIL	ZNF606	Q8WXB4	289
TRIL	YAF2	Q8IY57	287

IntAct

5 interactions, top by confidence:

A	B	Type	Score
TLR3	TRIL	psi-mi:“MI:0915”(physical association)	0.460
TRIL	TLR3	psi-mi:“MI:0403”(colocalization)	0.460
TRIL	MLLT11	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (2): TRIL (Affinity Capture-Western), TRIL (Affinity Capture-MS)

ESM2 similar proteins: A4IFA6, G3XA59, O02833, O08742, O08770, O14498, O15335, O93233, P02750, P22792, P35858, P35859, P40197, P70389, P83503, P98161, Q14392, Q149C3, Q27972, Q28680, Q3ZBI5, Q496Z2, Q5BK65, Q5I2M8, Q5IJ48, Q5NVQ6, Q5RF01, Q6EMK4, Q6GU68, Q6P7C4, Q6QMY6, Q6QNU9, Q6UY18, Q7L0X0, Q80ZD5, Q86WK7, Q86YC3, Q8BGX3, Q8BMT4, Q8BXQ3

Diamond homologs: A8WQH2, B1H234, E5DHB5, E9Q7T7, F7D3V9, G5EFX6, O14498, O75093, O75094, O88279, O88280, O94813, P0DKB5, P13224, P24014, P56400, Q04785, Q1ENI8, Q3UY51, Q4KLL3, Q50LG9, Q5R6T0, Q6NUI6, Q6RKD8, Q6ZSA7, Q7L0X0, Q7M6Z0, Q7Z2Q7, Q80TR4, Q80WD1, Q810B8, Q810C0, Q86UN3, Q8BGT1, Q8BXQ3, Q8IW52, Q96JA1, Q99M75, Q99PI8, Q9BZR6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	121
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

4 predictions. Top by Δscore:

Variant	Effect	Δscore
7:28955534:C:A	donor_gain	0.3500
7:28955533:T:TA	donor_gain	0.3400
7:28958122:AG:A	donor_gain	0.3300
7:28957438:G:A	donor_gain	0.3000

AlphaMissense

5142 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:28956235:C:A	W604C	1.000
7:28956235:C:G	W604C	1.000
7:28956964:C:A	W361C	1.000
7:28956964:C:G	W361C	1.000
7:28957696:G:C	N117K	1.000
7:28957696:G:T	N117K	1.000
7:28957712:A:G	L112P	1.000
7:28957768:G:C	N93K	1.000
7:28957768:G:T	N93K	1.000
7:28957769:T:A	N93I	1.000
7:28957778:A:G	L90P	1.000
7:28957835:A:T	I71K	1.000
7:28957840:G:C	N69K	1.000
7:28957840:G:T	N69K	1.000
7:28957841:T:A	N69I	1.000
7:28957924:G:C	C41W	1.000
7:28957926:A:G	C41R	1.000
7:28956038:C:T	C670Y	0.999
7:28956039:A:G	C670R	0.999
7:28956067:G:C	C660W	0.999
7:28956068:C:T	C660Y	0.999
7:28956069:A:G	C660R	0.999
7:28956237:A:G	W604R	0.999
7:28956237:A:T	W604R	0.999
7:28956848:T:C	Y400C	0.999
7:28956878:C:G	C390S	0.999
7:28956879:A:G	C390R	0.999
7:28956879:A:T	C390S	0.999
7:28956928:C:A	W373C	0.999
7:28956928:C:G	W373C	0.999

dbSNP variants (sampled 300 via entrez): RS1000458439 (7:28954645 G>A), RS1001652531 (7:28955396 C>A), RS1002025809 (7:28955076 T>G), RS1002499652 (7:28959451 G>A), RS1003211117 (7:28959475 C>T), RS1003431999 (7:28959167 T>A,C), RS1004577716 (7:28958877 G>T), RS1004631529 (7:28958609 C>G), RS1005245641 (7:28955947 C>G,T), RS1005611516 (7:28959686 A>T), RS1006211472 (7:28958339 G>A), RS1006521 (7:28956604 G>A), RS1006962051 (7:28953084 T>C), RS1007451652 (7:28958988 C>A,T), RS1008129029 (7:28953971 C>T)

Disease associations

OMIM: gene MIM:613356 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST008027_2	Smoking behaviour (cigarettes smoked per day)	6.000000e-09
GCST008027_5	Smoking behaviour (cigarettes smoked per day)	9.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006525	cigarettes per day measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases expression, increases methylation, affects expression	6
trichostatin A	affects cotreatment, increases expression, decreases expression	4
Estradiol	affects cotreatment, decreases expression	2
Nickel	decreases expression	2
Tretinoin	increases expression	2
aminomethylphosphonic acid (AMPA)	decreases expression	1
testosterone enanthate	affects expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	decreases expression	1
sodium arsenite	decreases expression	1
ferrous chloride	decreases expression	1
pentanal	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
2,2’,4,4’,5-brominated diphenyl ether	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
MRK 003	decreases expression	1
MT19c compound	decreases expression	1
Arsenic Trioxide	decreases expression	1
Acetaminophen	increases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Catechin	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Phenylmercuric Acetate	affects cotreatment, decreases expression	1
Urethane	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
2,4-Dichlorophenoxyacetic Acid	decreases expression	1
Antirheumatic Agents	increases expression	1

Clinical trials (associated diseases)

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