TOLLIP

Summary

TOLLIP (toll interacting protein, HGNC:16476) is a protein-coding gene on chromosome 11p15.5, encoding Toll-interacting protein (Q9H0E2). Component of the signaling pathway of IL-1 and Toll-like receptors.

This gene encodes a ubiquitin-binding protein that interacts with several Toll-like receptor (TLR) signaling cascade components. The encoded protein regulates inflammatory signaling and is involved in interleukin-1 receptor trafficking and in the turnover of IL1R-associated kinase. Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 54472 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 54 total
• MANE Select transcript: NM_019009

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16476
Approved symbol	TOLLIP
Name	toll interacting protein
Location	11p15.5
Locus type	gene with protein product
Status	Approved
Aliases	IL-1RAcPIP
Ensembl gene	ENSG00000078902
Ensembl biotype	protein_coding
OMIM	606277
Entrez	54472

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 11 protein_coding, 4 protein_coding_CDS_not_defined, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000263646, ENST00000317204, ENST00000525159, ENST00000527085, ENST00000527638, ENST00000527746, ENST00000527886, ENST00000527938, ENST00000528719, ENST00000530506, ENST00000530541, ENST00000530821, ENST00000532551, ENST00000863435, ENST00000863436, ENST00000863437, ENST00000961564, ENST00000961565

RefSeq mRNA: 5 — MANE Select: NM_019009 NM_001318512, NM_001318514, NM_001318515, NM_001318516, NM_019009

CCDS: CCDS7723, CCDS81532, CCDS81533, CCDS81534

Canonical transcript exons

ENST00000317204 — 6 exons

Exon	Start	End
ENSE00000690373	1286002	1286092
ENSE00001319112	1288624	1288776
ENSE00001339630	1274371	1277253
ENSE00001557938	1309466	1309632
ENSE00003531285	1290227	1290409
ENSE00003641486	1295645	1295794

Expression profiles

Bgee: expression breadth ubiquitous, 263 present calls, max score 97.38.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 39.0204 / max 330.4600, expressed in 1817 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
117965	34.4303	1815
117964	4.5509	1575
117963	0.0201	8
117960	0.0191	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	97.38	gold quality
anterior cingulate cortex	UBERON:0009835	96.84	gold quality
cingulate cortex	UBERON:0003027	96.78	gold quality
prefrontal cortex	UBERON:0000451	96.66	gold quality
lower esophagus mucosa	UBERON:0035834	96.22	gold quality
left testis	UBERON:0004533	96.03	gold quality
right testis	UBERON:0004534	95.91	gold quality
frontal cortex	UBERON:0001870	95.67	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	95.66	gold quality
right lobe of liver	UBERON:0001114	95.64	gold quality
neocortex	UBERON:0001950	95.41	gold quality
esophagus mucosa	UBERON:0002469	95.13	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.13	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.12	gold quality
amygdala	UBERON:0001876	95.03	gold quality
cerebellar hemisphere	UBERON:0002245	94.99	gold quality
cerebellar cortex	UBERON:0002129	94.92	gold quality
skin of leg	UBERON:0001511	94.87	gold quality
skin of abdomen	UBERON:0001416	94.16	gold quality
cerebral cortex	UBERON:0000956	94.13	gold quality
adenohypophysis	UBERON:0002196	94.10	gold quality
testis	UBERON:0000473	93.82	gold quality
gastrocnemius	UBERON:0001388	93.77	gold quality
cerebellum	UBERON:0002037	93.77	gold quality
middle temporal gyrus	UBERON:0002771	93.63	gold quality
nucleus accumbens	UBERON:0001882	93.46	gold quality
telencephalon	UBERON:0001893	93.42	gold quality
temporal lobe	UBERON:0001871	93.33	gold quality
superior frontal gyrus	UBERON:0002661	93.21	gold quality
forebrain	UBERON:0001890	93.05	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ELF1

miRNA regulators (miRDB)

106 targeting TOLLIP, 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-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481

Literature-anchored findings (GeneRIF, showing 40)

• Overexpression of Tollip inhibits NF-kappa B activation in response to Toll-like receptor-2 and Toll-like receptor-4 signaling in vitro. (PMID:11441107)
• Here we report that Tollip also associates directly with TLR2 and TLR4 and plays an inhibitory role in TLR-mediated cell activation (PMID:11751856)
• a Tom1-Tollip complex functions as a factor that links polyubiquitinated proteins to clathrin (PMID:14563850)
• Tollip and Tom1 form a complex and regulate endosomal trafficking of ubiquitinated proteins (PMID:15047686)
• following stimulation by exogenous CD26, Tollip and IRAK-1 dissociate from caveolin-1, and IRAK-1 is then phosphorylated in the cytosol, leading to the upregulation of CD86 via activation of NF-kappaB (PMID:16107720)
• Tollip is required for sorting of IL-1RI at late endosomes. (PMID:17113392)
• Variation in the TOLLIP gene may play a role in the pathogenesis of AD. (PMID:17362526)
• Expression of TLR-8, but not Tollip, is highly up-regulated in the colonic epithelium from patients with active IBD (PMID:18985539)
• Significant & strong 2- & 3-locus interactions between SNPs in TOLLIP (rs4963060), TLR4 (rs6478317) & IRAK1 (rs1059703)were associated with the response to whole-cell vaccine pertussis vaccination in 490 1-yr-old children. (PMID:18987746)
• DSCR1-1S isoform positively modulates IL-1R-mediated signaling pathways by regulating Tollip/IRAK-1/TRAF6 complex formation. (PMID:19716405)
• Our findings indicated that the variants in TOLLIP were significantly associated with sepsis susceptibility in the Chinese Han population. (PMID:21219635)
• Data show that knockdown of Tollip reduces CNF1-induced Rac1-dependent UPEC entry. (PMID:21291504)
• These findings suggest that basic residues of the C2 domain mediate membrane targeting of Tollip by interaction with phosphoinositides, which contribute to the observed partition of the protein in different subcellular compartments. (PMID:21294713)
• the results indicate that insufficient O-GlcNAc modification prevents Elf-1-mediated transcriptional repression and thereby upregulates Tollip gene expression in intestinal epithelial cells. (PMID:21867680)
• located in the cytoplasm of cytotrophoblasts in the first-trimester placental tissues (PMID:22582869)
• These data demonstrate that TOLLIP has an anti-inflammatory effect on TLR2 and TLR4 signaling in humans (PMID:22778396)
• Tollip cooperates with Smad7 to modulate intracellular trafficking and degradation of ubiquitinated TbetaRI, whereby negatively regulates TGF-beta signaling pathway. (PMID:23027871)
• in the absence of polyubiquitinated cargo, the dual binding of ubiquitin partitions Tollip into membrane-bound and membrane-free states, a function that contributes to the engagement of Tollip in both membrane trafficking and cytosolic pathways. (PMID:23880770)
• negative regulator of pathological cardiac hypertrophy by blocking the AKT signalling pathway (PMID:24285748)
• Just the individuals with genotype C/C of rs3750920 of the TOLLIP have a trend of protective effect to developing lepromatous leprosy . (PMID:24294608)
• Tollip depletion causes cytotoxicity toward polyQ proteins, whereas Tollip overexpression clears human cells from Huntington’s disease-linked polyQ proteins by autophagy; Tollip is a Functional Homolog of Yeast Cue5. (PMID:25042851)
• Which is achieved by elevated level of toll-interacting protein (TOLLIP) in presence of porin. (PMID:25152369)
• The MUC5B promoter polynmorphism, TOLLIP, is a strong risk factor for idiopathic pulmonary fibrosis in a Mexican population but is very rare in a Korean population. (PMID:25275363)
• TOLLIP contributes to mortality following myocardial infarction through promoting inflammation and apoptosis (PMID:25765712)
• Study shows that host factor Tollip inhibits HIV LTR-driven gene expression by suppressing NF-kappaB activation revealing its novel role in modulating HIV-1 infection. (PMID:25915421)
• Tollip acts as a novel modulator of I/R injury by promoting neuronal apoptosis and ischaemic inflammation, which are largely mediated by suppression of Akt signalling. (PMID:26011492)
• The two polymorphisms, rs5743899 and rs3750920, in the TOLLIP gene are independently associated with an increased risk of developing cutaneous leishmaniasis (CL). (PMID:26107286)
• we identify a novel function of Tollip in regulating the canonical Wnt pathway which is evolutionarily conserved between fish and humans. Tollip-mediated inhibition of Wnt signaling may contribute to embryonic development and to carcinogenesis. (PMID:26110841)
• Tom1 modulates binding of Tollip to phosphatidylinositol 3-phosphate via a coupled folding and binding mechanism. (PMID:26320582)
• TOLLIP encodes toll-interacting protein (TOLLIP), which is an inhibitory adaptor protein acting downstream from the toll-like receptors (TLRs). Read More: http://www.atsjournals.org/doi/full/10.1164/rccm.201505-1010OC#.VwqiYdLrvyA (PMID:26331942)
• Observed expression patterns of several TLR inhibitory proteins with a noticeable suppression in expression of two of these; PPARgamma and TOLLIP in both ulcerative colitis and Crohn’s disease and in both active and inactive disease states. (PMID:26462859)
• These data suggest that M. leprae upregulates IL-1Ra by a TOLLIP-dependent mechanism; inhibition of TOLLIP may decrease an individual’s susceptibility to leprosy and offer a novel therapeutic target for IL-1-dependent diseases. (PMID:26610735)
• Variants in the TOLLIP gene are associated with higher circulating PAI-1 plasma levels and association with clinical Primary Graft Dysfunction Risk. (PMID:26663441)
• Toll-interacting protein rs5743867 polymorphism tends to decrease the risk of sepsis in infants undergoing complex open heart surgery. (PMID:27002100)
• Knock-down of Tollip promotes HIV-1 reactivation from latency. (PMID:27181351)
• pharmacogenetic analysis of patients enrolled in an idiopathic pulmonary fibrosis (IPF) clinical trial identified a variant within TOLLIP to be associated with differential response to N-acetylcysteine therapy. (PMID:27253772)
• Our data suggest that Tollip SNP rs5743899 may predict varying airway response to RV infection in asthma. (PMID:27513438)
• Data reveal a novel mechanism in Tollip alteration that underlies the inflamed and incompetent polarization of neutrophils leading to severe outcomes of septic colitis. (PMID:27703259)
• Toll-interacting protein (TOLLIP) is a ubiquitin-binding protein that regulates innate immune responses. (PMID:28463648)
• study to examine potential associations between a selection of SNPs in the genes encoding TLR2 and TOLLIP, and predisposition, severity and outcome of Staphylococcus aureus bloodstream infections (SABSI); the TLR2 and TOLLIP polymorphisms were not associated with susceptibility to SABSI, severity, 30-day all-cause mortality, or SABSI caused by the clonal complex 30 genotype (PMID:28736863)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tollip	ENSDARG00000098486
mus_musculus	Tollip	ENSMUSG00000025139
rattus_norvegicus	Tollip	ENSRNOG00000019861
caenorhabditis_elegans	tli-1	WBGENE00006578

Protein

Protein identifiers

Toll-interacting protein — Q9H0E2 (reviewed: Q9H0E2)

All UniProt accessions (7): Q9H0E2, E7EN89, E9PNS3, E9PP67, E9PQ25, F2Z2Y8, Q6FIE9

UniProt curated annotations — full annotation on UniProt →

Function. Component of the signaling pathway of IL-1 and Toll-like receptors. Inhibits cell activation by microbial products. Recruits IRAK1 to the IL-1 receptor complex. Inhibits IRAK1 phosphorylation and kinase activity. Connects the ubiquitin pathway to autophagy by functioning as a ubiquitin-ATG8 family adapter and thus mediating autophagic clearance of ubiquitin conjugates. The TOLLIP-dependent selective autophagy pathway plays an important role in clearance of cytotoxic polyQ proteins aggregates. In a complex with TOM1, recruits ubiquitin-conjugated proteins onto early endosomes. Binds to phosphatidylinositol 3-phosphate (PtdIns(3)P).

Subunit / interactions. Oligomerizes. Interacts (via C-terminus) with TLR2 and the TLR4-MD2 complex. Exists as complex with IRAK1 in unstimulated cells. Upon IL-1 signaling, binds to the activated IL-1 receptor complex containing IL-1RI, IL-1RacP and the adapter protein MyD88, where it interacts with the TIR domain of IL-1RacP. MyD88 then triggers IRAK1 autophosphorylation, which in turn leads to the dissociation of IRAK1 from TOLLIP and IL-1RAcP. Found in a complex with TOM1; interacts (via N-terminus) with TOM1 (via GAT domain); the interactions leads to TOM1-recruitment to endosomes and inhibition of TOLLIP binding to PtdIns(3)P. Interacts with TOM1L2. Interacts with ATG8 family proteins (via AIM motifs). Interacts (via CUE domain) with ubiquitin. Interacts with LRBA. Interacts with ZNF268; this interaction leads to degradation by Tollip-mediated selective autophagy system.

Subcellular location. Cytoplasm. Endosome. Early endosome.

Post-translational modifications. Phosphorylated by IRAK1 upon stimulation by IL-1 or microbial products.

Domain organisation. Both ATG8-interaction motifs (AIM1 and AIM2) are required for the association with ATG8 family proteins. The N-terminal TOM1-binding domain (residues 1-53) is a disordered domain that partially folds when bound to the GAT domain of TOM1.

Similarity. Belongs to the tollip family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H0E2-1	1	yes
Q9H0E2-2	2

RefSeq proteins (5): NP_001305441, NP_001305443, NP_001305444, NP_001305445, NP_061882* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR003892	CUE	Domain
IPR009060	UBA-like_sf	Homologous_superfamily
IPR035892	C2_domain_sf	Homologous_superfamily
IPR037301	Tollip_C2	Domain
IPR041799	TOLIP_CUE	Domain

Pfam: PF00168, PF02845

UniProt features (24 total): mutagenesis site 5, strand 3, helix 3, sequence conflict 2, domain 2, short sequence motif 2, sequence variant 2, initiator methionine 1, chain 1, turn 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1WGL	SOLUTION NMR
2N31	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H0E2-F1	81.26	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): 2

Mutagenesis-validated functional residues (5):

Position	Phenotype
9	reduced interaction with tom1; when associated with ala-12.
12	reduced interaction with tom1; when associated with ala-9.
20	reduced interaction with tom1; when associated with ala-23.
21	reduced interaction with tom1.
23	reduced interaction with tom1; when associated with ala-20.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation
R-HSA-9020702	Interleukin-1 signaling

MSigDB gene sets: 218 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GOBP_EPITHELIUM_DEVELOPMENT, REACTOME_INNATE_IMMUNE_SYSTEM, TGCGCANK_UNKNOWN, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOCC_SECRETORY_GRANULE, GOBP_REGULATION_OF_PROTEIN_SUMOYLATION, PID_IL1_PATHWAY, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, CAGCTG_AP4_Q5, GOBP_PEPTIDYL_LYSINE_MODIFICATION, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_RESPONSE_TO_INTERLEUKIN_1

GO Biological Process (12): ubiquitin-dependent protein catabolic process (GO:0006511), autophagy (GO:0006914), inflammatory response (GO:0006954), signal transduction (GO:0007165), phosphorylation (GO:0016310), epithelial cell differentiation (GO:0030855), positive regulation of protein sumoylation (GO:0033235), protein localization to endosome (GO:0036010), innate immune response (GO:0045087), leukocyte activation (GO:0045321), interleukin-1-mediated signaling pathway (GO:0070498), immune system process (GO:0002376)

GO Molecular Function (9): interleukin-1, type I receptor binding (GO:0005150), kinase binding (GO:0019900), ubiquitin conjugating enzyme binding (GO:0031624), ubiquitin protein ligase binding (GO:0031625), SUMO binding (GO:0032183), Toll-like receptor binding (GO:0035325), ubiquitin binding (GO:0043130), molecular adaptor activity (GO:0060090), protein binding (GO:0005515)

GO Cellular Component (12): extracellular region (GO:0005576), cytoplasm (GO:0005737), early endosome (GO:0005769), cytosol (GO:0005829), nuclear body (GO:0016604), extrinsic component of plasma membrane (GO:0019897), protein-containing complex (GO:0032991), azurophil granule lumen (GO:0035578), specific granule lumen (GO:0035580), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), endosome (GO:0005768)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Innate Immune System	1
Interleukin-1 family signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
ubiquitin-like protein binding	2
binding	2
cytoplasm	2
secretory granule lumen	2
protein ubiquitination	1
modification-dependent protein catabolic process	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
defense response	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
phosphate-containing compound metabolic process	1
cell differentiation	1
epithelium development	1
protein sumoylation	1
regulation of protein sumoylation	1
positive regulation of protein modification by small protein conjugation or removal	1
protein localization to organelle	1
immune response	1
defense response to symbiont	1
cell activation	1
immune system process	1
cytokine-mediated signaling pathway	1
cellular response to interleukin-1	1
biological_process	1
interleukin-1 receptor binding	1
enzyme binding	1
ubiquitin-like protein conjugating enzyme binding	1
ubiquitin-like protein ligase binding	1
signaling receptor binding	1
molecular_function	1
intracellular anatomical structure	1
endosome	1
nucleoplasm	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1802 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TOLLIP	IRAK1	P51617	994
TOLLIP	MYD88	P78397	993
TOLLIP	TOM1	O60784	989
TOLLIP	TLR4	O00206	987
TOLLIP	TLR2	O60603	967
TOLLIP	IL1R1	P14778	891
TOLLIP	IRAK4	Q9NWZ3	887
TOLLIP	TRAF6	Q9Y4K3	812
TOLLIP	SIGIRR	Q6IA17	743
TOLLIP	IRAK3	Q9Y616	707
TOLLIP	IL1B	P01584	694
TOLLIP	IRAK2	O43187	690
TOLLIP	PELI1	Q96FA3	690
TOLLIP	TAB2	Q9NYJ8	672
TOLLIP	SQSTM1	Q13501	666

IntAct

262 interactions, top by confidence:

A	B	Type	Score
TOM1	TOLLIP	psi-mi:“MI:0915”(physical association)	0.890
TOLLIP	TOM1	psi-mi:“MI:0915”(physical association)	0.890
TOLLIP	DAZAP2	psi-mi:“MI:0915”(physical association)	0.840
DAZAP2	TOLLIP	psi-mi:“MI:0915”(physical association)	0.840
RHOXF2	TOLLIP	psi-mi:“MI:0915”(physical association)	0.800
TOLLIP	TOM1L1	psi-mi:“MI:0915”(physical association)	0.800
TOLLIP	NTAQ1	psi-mi:“MI:0915”(physical association)	0.670
RBPMS	TOLLIP	psi-mi:“MI:0915”(physical association)	0.670
NTAQ1	TOLLIP	psi-mi:“MI:0915”(physical association)	0.670
TOLLIP	RBPMS	psi-mi:“MI:0915”(physical association)	0.670
PHAF1	TOLLIP	psi-mi:“MI:0915”(physical association)	0.670
ARRDC3	TOLLIP	psi-mi:“MI:0915”(physical association)	0.670
ATXN1	TOLLIP	psi-mi:“MI:0915”(physical association)	0.670
DAB1	TOLLIP	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (479): TOLLIP (Two-hybrid), TOLLIP (Two-hybrid), TOLLIP (Two-hybrid), TOLLIP (Two-hybrid), TOLLIP (Two-hybrid), TOLLIP (Two-hybrid), WDYHV1 (Two-hybrid), PRR20A (Two-hybrid), TOLLIP (Reconstituted Complex), TOLLIP (Reconstituted Complex), TOLLIP (Reconstituted Complex), TOLLIP (Reconstituted Complex), TOLLIP (Reconstituted Complex), TOLLIP (Two-hybrid), RHOXF2 (Two-hybrid)

ESM2 similar proteins: A1ZBD6, A2RUW1, B0W3L6, B1V8A0, B5X370, B7WN72, C1BZR1, F1M3L7, O04133, O17453, O42632, O61742, O70209, P42731, P51140, P87253, P90727, P90978, Q00078, Q08509, Q12929, Q174R2, Q2LGB5, Q3B8H2, Q3SYZ8, Q4LBC7, Q4LBC8, Q4WVG0, Q5F3S2, Q5R4H4, Q5ZK05, Q61AP6, Q65XV7, Q6CFT4, Q6DFR0, Q6H7J5, Q6INE3, Q6NZZ9, Q7Q2B7, Q7ZV43

Diamond homologs: A2RUW1, B5X370, C1BZR1, Q2LGB5, Q3B8H2, Q4LBC7, Q4LBC8, Q5ZK05, Q6DFR0, Q6INE3, Q7ZV43, Q9H0E2, Q9QZ06, Q54Y08

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
IL1RAP	“down-regulates activity”	TOLLIP	binding
TOLLIP	“down-regulates activity”	IRAK1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	35
Likely benign	2
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1906 predictions. Top by Δscore:

Variant	Effect	Δscore
11:1288619:CTCA:C	donor_loss	1.0000
11:1288620:TCACC:T	donor_loss	1.0000
11:1288621:CACCG:C	donor_loss	1.0000
11:1288622:A:AC	donor_gain	1.0000
11:1288622:ACCGC:A	donor_loss	1.0000
11:1288623:C:CC	donor_gain	1.0000
11:1288623:CCG:C	donor_gain	1.0000
11:1288773:CTCT:C	acceptor_gain	1.0000
11:1288775:CT:C	acceptor_gain	1.0000
11:1288777:C:CC	acceptor_gain	1.0000
11:1288777:C:T	acceptor_loss	1.0000
11:1295793:ACC:A	acceptor_loss	1.0000
11:1295795:CT:C	acceptor_loss	1.0000
11:1295796:T:C	acceptor_loss	1.0000
11:1295804:C:CT	acceptor_gain	1.0000
11:1295805:G:T	acceptor_gain	1.0000
11:1277249:CATCC:C	acceptor_gain	0.9900
11:1277251:TCC:T	acceptor_gain	0.9900
11:1277252:CC:C	acceptor_gain	0.9900
11:1277252:CCC:C	acceptor_gain	0.9900
11:1277253:CC:C	acceptor_gain	0.9900
11:1277254:C:CC	acceptor_gain	0.9900
11:1277254:CT:C	acceptor_loss	0.9900
11:1277255:T:A	acceptor_loss	0.9900
11:1288655:T:TA	donor_gain	0.9900
11:1288772:GCTCT:G	acceptor_gain	0.9900
11:1288773:CTCTC:C	acceptor_gain	0.9900
11:1288774:TCT:T	acceptor_gain	0.9900
11:1288774:TCTCT:T	acceptor_gain	0.9900
11:1288775:CTC:C	acceptor_gain	0.9900

AlphaMissense

1795 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:1288653:C:G	G164R	1.000
11:1288676:C:T	G156E	1.000
11:1288748:G:T	A132D	1.000
11:1290293:C:A	W100C	1.000
11:1290293:C:G	W100C	1.000
11:1290294:C:G	W100S	1.000
11:1290295:A:G	W100R	1.000
11:1290295:A:T	W100R	1.000
11:1290300:G:T	P98H	1.000
11:1290362:G:C	C77W	1.000
11:1288640:A:G	L168P	0.999
11:1288646:A:T	I166N	0.999
11:1288652:C:A	G164V	0.999
11:1288652:C:T	G164D	0.999
11:1288653:C:A	G164C	0.999
11:1288656:C:T	E163K	0.999
11:1288668:C:A	G159W	0.999
11:1288676:C:A	G156V	0.999
11:1288677:C:A	G156W	0.999
11:1288677:C:G	G156R	0.999
11:1288677:C:T	G156R	0.999
11:1288682:A:G	L154P	0.999
11:1288682:A:T	L154Q	0.999
11:1288692:A:G	W151R	0.999
11:1288692:A:T	W151R	0.999
11:1288746:A:G	W133R	0.999
11:1288746:A:T	W133R	0.999
11:1288749:C:G	A132P	0.999
11:1288751:A:T	I131N	0.999
11:1288760:T:A	D128V	0.999

dbSNP variants (sampled 300 via entrez): RS1000040467 (11:1308036 C>T), RS1000114589 (11:1288949 G>A), RS1000128779 (11:1295876 C>T), RS1000212007 (11:1284791 A>C), RS1000254715 (11:1299157 C>T), RS1000451606 (11:1289944 A>G), RS1000483365 (11:1304368 C>T), RS1000485871 (11:1303727 T>C), RS1000537447 (11:1276695 G>A), RS1000589909 (11:1276796 A>G), RS1000646276 (11:1309505 G>A,T), RS1000679073 (11:1295092 G>A,C,T), RS1000773288 (11:1289793 G>A,C), RS1000953091 (11:1285630 G>A), RS1001146511 (11:1281570 G>A)

Disease associations

OMIM: gene MIM:606277 | disease phenotypes: MIM:606963, MIM:178500

GenCC curated gene-disease

Mondo (3): chronic obstructive pulmonary disease (MONDO:0005002), interstitial lung disease 2 (MONDO:0800497), combined pulmonary fibrosis-emphysema syndrome (MONDO:0017591)

Orphanet (3): Idiopathic pulmonary fibrosis (Orphanet:2032), Acute interstitial pneumonia (Orphanet:79126), Combined pulmonary fibrosis-emphysema syndrome (Orphanet:300564)

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001974_1	Idiopathic pulmonary fibrosis	2.000000e-50
GCST001974_4	Idiopathic pulmonary fibrosis	1.000000e-12
GCST001974_5	Idiopathic pulmonary fibrosis	3.000000e-11
GCST010277_7	Gout	4.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0000768	idiopathic pulmonary fibrosis

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D029424	Pulmonary Disease, Chronic Obstructive	C08.381.495.389; C23.550.291.500.875

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs3750920	Efficacy	3	acetylcysteine	Pulmonary Fibrosis

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3750920	TOLLIP	3	1.75	1	acetylcysteine
rs5743854	TOLLIP		0.00	0
rs5743890	TOLLIP		0.00	0
rs5743894	TOLLIP		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases methylation, decreases expression, increases expression	4
Tobacco Smoke Pollution	affects expression, increases expression	3
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
Air Pollutants	affects expression, increases abundance, increases response to substance	2
Arsenic	affects cotreatment, increases abundance, increases expression, affects methylation	2
Vehicle Emissions	affects cotreatment, affects reaction, increases abundance, increases secretion, increases expression	2
Benzo(a)pyrene	affects methylation	2
Smoke	decreases expression	2
Particulate Matter	increases secretion, increases expression, affects cotreatment, affects reaction, increases abundance	2
aristolochic acid I	increases expression	1
GSK-J4	increases expression	1
bisphenol F	increases expression	1
2,4,6-tribromophenol	decreases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
titanium dioxide	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects localization, affects cotreatment, increases expression	1
decabromobiphenyl ether	decreases expression	1
butyraldehyde	decreases expression	1
tetrabromobisphenol A	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
ceric oxide	decreases expression	1
zinc sulfide	increases expression, affects cotreatment	1
pentanal	decreases expression	1
cadmium selenide	increases expression, affects cotreatment	1
cobalt oxide	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9UM	Ubigene HEK293 TOLLIP KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00120978	PHASE4	UNKNOWN	Can Advair and Flovent Reduce Systemic Inflammation Related to Chronic Obstructive Pulmonary Disease (COPD)? A Multi-Center Randomized Controlled Trial
NCT00134979	PHASE4	COMPLETED	Formoterol Certihaler, Tiotropium HandiHaler and Tiotropium HandiHaler in Combination With Formoterol Certihaler in Patients With Stable Chronic Obstructive Pulmonary Disease
NCT00158847	PHASE4	TERMINATED	Modification Of Disease Outcome In COPD
NCT00170222	PHASE4	COMPLETED	Placebo Versus Antibiotics in Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD)
NCT00175565	PHASE4	COMPLETED	Inhaled Steroid Reduces Systemic Inflammation in COPD
NCT00181207	PHASE4	COMPLETED	Airway Clearance for Prevention of Chronic Obstructive Pulmonary Disease (COPD) Exacerbation
NCT00186706	PHASE4	COMPLETED	Selenium Supplementation in Chronic Obstructive Pulmonary Disease (COPD) Patients
NCT00190437	PHASE4	COMPLETED	ANTEAB: a Study of Early Antibiotherapy in the ICU Management of Acute Exacerbations of COPD
NCT00202176	PHASE4	COMPLETED	Effects of Bronchodilators in Mild Chronic Obstructive Pulmonary Disease (COPD)
NCT00202189	PHASE4	COMPLETED	Effects of Inhaled Corticosteroids in Chronic Obstructive Pulmonary Disease (COPD)
NCT00232674	PHASE4	COMPLETED	Efficacy Study of the Effect of Budesonide on Emphysema
NCT00288548	PHASE4	UNKNOWN	Metoprolol and Formoterol in Chronic Obstructive Pulmonary Disease (COPD)
NCT00291408	PHASE4	WITHDRAWN	Effect of Symbicort on HAT and HDAC in Sputum Macrophages of COPD
NCT00291460	PHASE4	UNKNOWN	Inspiratory Muscle Training in Hypercapnic COPD
NCT00292838	PHASE4	COMPLETED	Relative Potency of Inhaled Corticosteroids
NCT00311961	PHASE4	COMPLETED	Intravenous Versus Oral Administration of Prednisolone in Exacerbations of Chronic Obstructive Pulmonary Disease (COPD)
NCT00316992	PHASE4	COMPLETED	Safety of Ramelteon in Subjects With Chronic Obstructive Pulmonary Disease
NCT00331656	PHASE4	UNKNOWN	Comparative Study of Non-Invasive Mask Ventilation vs Cuirass Ventilation in Patients With Acute Respiratory Failure.
NCT00335621	PHASE4	WITHDRAWN	Replacement of Nebulised Ipratropium With Inhaled Tiotropium in Stable Chronic Obstructive Pulmonary Disease (COPD)
NCT00354354	PHASE4	COMPLETED	Bronchodilators and Oxygen Kinetics With Exercise in Chronic Obstructive Pulmonary Disease (COPD) Patients
NCT00379028	PHASE4	COMPLETED	Airway Clearance Study
NCT00405236	PHASE4	COMPLETED	Effect of Tiotropium on Inflammation and Exacerbations in COPD
NCT00412204	PHASE4	COMPLETED	Study to Evaluate the Effects of Tiotropium Bromide on Chronic Obstructive Pulmonary Disease (COPD) During Exercise
NCT00424528	PHASE4	COMPLETED	Efficacy Safety Study of Arformoterol/Tiotropium Combination Versus Either Therapy Alone in Chronic Obstructive Pulmonary Disease (COPD)
NCT00440245	PHASE4	COMPLETED	Bronchoprotection of Salbutamol in Asthma and Chronic Obstructive Pulmonary Disease
NCT00440687	PHASE4	COMPLETED	Withdrawal of Inhaled Corticosteroids in Patients With COPD in Primary Care
NCT00489853	PHASE4	COMPLETED	Evaluation of Efficacy on Exercise Tolerance of Symbicort (Budesonide/Formoterol) Compared to Placebo and Oxis in Patients With Severe COPD
NCT00491803	PHASE4	COMPLETED	Sildenafil Effects on Pulmonary Haemodynamics and Gas Exchange in Chronic Obstructive Pulmonary Disease (COPD)
NCT00495586	PHASE4	COMPLETED	Effectiveness of Antibiotic Therapy for Exacerbations of Chronic Obstructive Pulmonary Disease
NCT00525564	PHASE4	COMPLETED	Effects of Salmeterol on Walking Capacity in Patients With COPD
NCT00532584	PHASE4	WITHDRAWN	Effect of Steroids on Gene Expression in the Healthy Smokers Lungs
NCT00542880	PHASE4	COMPLETED	Evaluation of Onset of Effect in Patients With Severe Chronic Obstructive Pulmonary Disease (COPD) Treated With Symbicort® Compared to Seretide®
NCT00561886	PHASE4	COMPLETED	Change of Inspiratory Peak Flow in COPD
NCT00569270	PHASE4	COMPLETED	Dynamic Hyperinflation and Tiotropium
NCT00571428	PHASE4	COMPLETED	Efficacy Safety Study of Arformoterol QD Dosing Versus BID Dosing in COPD
NCT00578968	PHASE4	COMPLETED	Cardiac Limitations in Chronic Obstructive Pulmonary Disease: Benefits of Bronchodilation
NCT00592033	PHASE4	COMPLETED	Effect of Oxygen in Normoxaemic COPD Patients Who Desaturate During Exercise
NCT00628225	PHASE4	COMPLETED	Smoking Cessation in Patients With COPD (SMOCC) in General Practice
NCT00633776	PHASE4	WITHDRAWN	Perforomist Versus Foradil Evaluated by Inspiratory Capacity and High Resolution Computed Tomography (HRCT)
NCT00639236	PHASE4	COMPLETED	Effectiveness and Safety of Inhaling Hypertonic Saline in Patients With Chronic Obstructive Pulmonary Disease