TICAM1

Summary

TICAM1 (TIR domain containing adaptor molecule 1, HGNC:18348) is a protein-coding gene on chromosome 19p13.3, encoding TIR domain-containing adapter molecule 1 (Q8IUC6). Involved in innate immunity against invading pathogens.

This gene encodes an adaptor protein containing a Toll/interleukin-1 receptor (TIR) homology domain, which is an intracellular signaling domain that mediates protein-protein interactions between the Toll-like receptors (TLRs) and signal-transduction components. This protein is involved in native immunity against invading pathogens. It specifically interacts with toll-like receptor 3, but not with other TLRs, and this association mediates dsRNA induction of interferon-beta through activation of nuclear factor kappa-B, during an antiviral immune response. Mutations in this gene are associated with encephalopathy, acute, infection-induced.

Source: NCBI Gene 148022 — RefSeq curated summary.

At a glance

• Gene–disease (curated): herpes simplex encephalitis, susceptibility to, 4 (Strong, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 443 total
• Phenotypes (HPO): 36
• MANE Select transcript: NM_182919

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18348
Approved symbol	TICAM1
Name	TIR domain containing adaptor molecule 1
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	TRIF, TICAM-1, MGC35334, PRVTIRB
Ensembl gene	ENSG00000127666
Ensembl biotype	protein_coding
OMIM	607601
Entrez	148022

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000248244, ENST00000868535

RefSeq mRNA: 4 — MANE Select: NM_182919 NM_001385678, NM_001385679, NM_001385680, NM_182919

CCDS: CCDS12136

Canonical transcript exons

ENST00000248244 — 2 exons

Exon	Start	End
ENSE00001433704	4815932	4818516
ENSE00001434277	4831614	4831712

Expression profiles

Bgee: expression breadth ubiquitous, 227 present calls, max score 96.14.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.4766 / max 384.2019, expressed in 1700 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
178496	13.9027	1693
178495	3.3070	987
178494	0.2668	103

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	96.14	gold quality
buccal mucosa cell	CL:0002336	91.32	gold quality
esophagus mucosa	UBERON:0002469	89.53	gold quality
granulocyte	CL:0000094	87.99	gold quality
mucosa of transverse colon	UBERON:0004991	86.73	gold quality
parotid gland	UBERON:0001831	86.43	silver quality
gastrocnemius	UBERON:0001388	85.04	gold quality
esophagus	UBERON:0001043	84.86	gold quality
ascending aorta	UBERON:0001496	84.04	gold quality
thoracic aorta	UBERON:0001515	83.98	gold quality
skin of abdomen	UBERON:0001416	83.75	gold quality
hindlimb stylopod muscle	UBERON:0004252	83.52	gold quality
body of stomach	UBERON:0001161	83.47	gold quality
right lobe of liver	UBERON:0001114	83.45	gold quality
skin of leg	UBERON:0001511	83.26	gold quality
descending thoracic aorta	UBERON:0002345	83.16	gold quality
muscle of leg	UBERON:0001383	83.10	gold quality
aorta	UBERON:0000947	82.91	gold quality
leukocyte	CL:0000738	82.76	gold quality
monocyte	CL:0000576	82.52	gold quality
right coronary artery	UBERON:0001625	82.45	gold quality
mononuclear cell	CL:0000842	82.37	gold quality
apex of heart	UBERON:0002098	82.26	gold quality
popliteal artery	UBERON:0002250	82.22	gold quality
tibial artery	UBERON:0007610	82.21	gold quality
duodenum	UBERON:0002114	81.93	gold quality
right lung	UBERON:0002167	81.88	gold quality
upper lobe of left lung	UBERON:0008952	81.71	gold quality
ectocervix	UBERON:0012249	81.62	gold quality
transverse colon	UBERON:0001157	81.59	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.10

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
CCL5	Activation

Upstream regulators (CollecTRI, top): IRF3, IRF6, NFKB, SP1, TRAF6

Literature-anchored findings (GeneRIF, showing 40)

• TRIF is identified and characterized as a novel adaptor protein containing the Toll/IL-1 receptor domain, with a specific role in TLR3 signaling. (PMID:12471095)
• identified an alternative adaptor, designated Toll-interleukin 1 receptor domain (TIR)-containing adaptor molecule (TICAM)-1, that can physically bind the TIR domain of TLR3 (PMID:12539043)
• LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF. (PMID:14517278)
• the adapter complex of TICAM-2 and TICAM-1 plays a crucial role in lipopolysaccharide-TLR4-mediated activation of IFN-beta (PMID:14519765)
• TRIF associates with TNF receptor-associated factor 6 (TRAF6) and TANK-binding kinase (TBK)-1 independently and activates two distinct transcription factors, NF-kappa B and IFN regulatory factor-3, respectively. (PMID:14530355)
• the TRIF-induced IFN-stimulated response element and NF-kappaB activation and apoptosis pathways are uncoupled (PMID:14739303)
• TRIF has a distal region with the ability to negatively regulate basal transcription & a proximal region containing an Sp1 site that confers approx. 75% of basal transcriptional activity. TRIF appears to be regulated primarily by NF-kappaB. (PMID:14960149)
• double-stranded RNA-induced TLR3/TRIF-mediated NF-kappaB and IRF3 activation diverge at TRIF (PMID:14982987)
• TRIF-induced ISRE and NF-kappaB activation are inhibited by PIASy (PMID:15251447)
• studies of the molecular properties of TRIF which contribute to its ability to function as a substrate for the NS3/4A protease; a polyproline II interaction with the 3(10) helix likely facilitates NS3/4A recognition of TRIF (PMID:15767257)
• TRIF-induced cell death required caspase activity initiated by the Fas/Apo-1-associated DD protein-caspase-8 axis (PMID:15814722)
• SARM associated with TRIF, and ‘knockdown’ of endogenous SARM expression by interfering RNA led to enhanced TRIF-dependent cytokine and chemokine induction. (PMID:16964262)
• the spatiotemporal mobilization of TICAM-1 in response to dsRNA and the formation of the TICAM-1 speckles containing RIP1 and NAP1 are important for the activation of the TLR3-TICAM-1 pathway. (PMID:17982077)
• activation and formation of TICAM-1 signalosomes with NF-kappaB and interferon regulatory factor-3 requires oligomerization induced at two different sites and RIP1 binding (PMID:18450748)
• PTP1B is a physiological negative regulator of TLR signaling via suppression of both MyD88- and TRIF-dependent production of proinflammatory cytokine and IFN-beta in macrophages. (PMID:18571728)
• Inactivation of Trif and Cardif can also occur through cellular caspases activated by various pro-apoptotic signals. (PMID:18756281)
• PKR, in addition to IPS-1 and IRF3 but not TRIF, was required for maximal type I IFN-beta induction and the induction of apoptosis by both transfected PRNAs and polyinosinic-polycytidylic acid. (PMID:19028691)
• dysregulation of TLR4-triggered MyD88- and TRIF-dependent signaling pathways and increased expression of negative regulators of TLR signaling in endotoxin-tolerant human monocytes. (PMID:19656901)
• Knockdown of BS69 resulted in a decrease of IFN-beta induction, suggesting that BS69 is a positive regulator for the TLR3-TICAM-1 pathway and negative regulatory properties in NF-kappaB activation. (PMID:19795416)
• The binding of TRAF2 and TRAF6 to TICAM-1 cooperatively activates the IFN-inducing pathway through ubiquitination of TICAM-1. (PMID:20047764)
• TRIS was associated with TRIF upon TLR3 activation by poly(I-C). These findings reveal an unexpected mechanism of TLR3-mediated signaling. (PMID:20200155)
• SARM-mediated inhibition may not be exclusively directed at TRIF or MyD88, but that SARM may also directly inhibit MAPK phosphorylation (PMID:20306472)
• Consistent with results for total tumor necrosis factor (TNF)-alpha messenger RNA (mRNA) levels, lipopolysaccharide-stimulated Trif transgenic and wild-type bone marrow-derived dendritic cells generate comparable amounts of TNF-alpha transcripts. (PMID:20375303)
• Data show that mutant TICAM-1 failed to recruit the IRF-3 kinase TBK1, resulting in lack of IRF-3 phosphorylation. (PMID:20418377)
• TRIF modulates TLR5-dependent responses by inducing proteolytic degradation of TLR5 (PMID:20452988)
• Silencing TRIF expression reduces TLR5-induced NFkappaB, JNK1/2, and ERK1/2 activation in human colonic epithelial cells. (PMID:20855887)
• TRIF protein induces soluble tumor necrosis factor receptor 1 (TNFR1) shedding via signaling from human airway epithelial cells (NCI-H292) with subsequent activation of two downstream pathways. (PMID:21148036)
• KSHV employs a novel mechanism to block the innate immunity by degrading TRIF protein. (PMID:21212282)
• RA synovium showed abundant expression of TLR. RA synovitis tissue seems to be responsive to TLR ligands. (PMID:21324962)
• Data indicate that CD300F is an active regulator of TLR-mediated macrophage activation through association with SHP-1 involving MyD88 and/or TRIF. (PMID:21536801)
• PLIC-1 is a novel inhibitor of the TLR3-Trif antiviral pathway by reducing the abundance of Trif (PMID:21695056)
• TRIF cleavage mediated by human enterovirus 71 3C protease may be a mechanism to impair type I interferon production in response to Toll-like receptor 3 (TLR3) activation. (PMID:21697485)
• These studies establish that MyD88 but not Trif signaling plays a critical role in mediating cardiac dysfunction, systemic inflammation, and mortality during polymicrobial sepsis (PMID:21792053)
• show that hBD3 reduces NF-kappaB signaling in cells transfected with MyD88 or TRIF (PMID:21809339)
• Hepatitis A virus inhibits TLR3 signaling by reducing abundance of the adaptor protein TRIF. (PMID:21931545)
• The host TICAM-1 transgene pathway is essential for antiviral responses that suppress poliovirus infection, which is exacerbated in TICAM-1-deficient poliovirus receptor-bearing mice. (PMID:21998457)
• regulation of the TLR3/TRIF-mediated pathway required the combined action of SHP-1 and SHP-2, which could be accomplished by CD300f but not CD300a (PMID:22043923)
• The TLR2/4 ligand biglycan enhances antigen-specific T cell priming via MyD88 and Toll-like receptor adapter molecule TRIF pathways, triggering autoimmune perimyocarditis in transgenic mice. (PMID:22095710)
• Susceptibility to herpes simplex encephalitis is caused by TRIF nonsense (autosomal recessive) TRIF deficiency or a missense mutation (autosomal dominant). TRIf is needed for TLR3-dependent interferon synthesis. (PMID:22105173)
• TRIF may play an important role in the pathogenesis of antiphospholipid syndrome. (PMID:22152804)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ticam1	ENSMUSG00000047123
rattus_norvegicus	Ticam1	ENSRNOG00000080915

Protein

Protein identifiers

TIR domain-containing adapter molecule 1 — Q8IUC6 (reviewed: Q8IUC6)

Alternative names: Proline-rich, vinculin and TIR domain-containing protein B, Putative NF-kappa-B-activating protein 502H, Toll-interleukin-1 receptor domain-containing adapter protein inducing interferon beta

All UniProt accessions (1): Q8IUC6

UniProt curated annotations — full annotation on UniProt →

Function. Involved in innate immunity against invading pathogens. Adapter used by TLR3, TLR4 (through TICAM2) and TLR5 to mediate NF-kappa-B and interferon-regulatory factor (IRF) activation, and to induce apoptosis. Ligand binding to these receptors results in TRIF recruitment through its TIR domain. Distinct protein-interaction motifs allow recruitment of the effector proteins TBK1, TRAF6 and RIPK1, which in turn, lead to the activation of transcription factors IRF3 and IRF7, NF-kappa-B and FADD respectively. Phosphorylation by TBK1 on the pLxIS motif leads to recruitment and subsequent activation of the transcription factor IRF3 to induce expression of type I interferon and exert a potent immunity against invading pathogens. Component of a multi-helicase-TICAM1 complex that acts as a cytoplasmic sensor of viral double-stranded RNA (dsRNA) and plays a role in the activation of a cascade of antiviral responses including the induction of pro-inflammatory cytokines.

Subunit / interactions. Homodimer. Found in a multi-helicase-TICAM1 complex at least composed of DHX36, DDX1, DDX21 and TICAM1; this complex exists in resting cells with or without poly(I:C) RNA ligand stimulation. Interacts (via TIR domain) with DDX21 (via C-terminus). Interacts (via TIR domain) with DHX36 (via C-terminus). Interacts with AZI2 and IRF7. Interacts with TICAM2 in TLR4 recruitment. Interaction with PIAS4 inhibits the TICAM1-induced NF-kappa-B, IRF and IFNB1 activation. Interacts with IKBKB and IKBKE. Interaction with SARM1 blocks TICAM1-dependent transcription factor activation. Interacts with TRAF3. Interacts (when phosphorylated) with IRF3; following activation and phosphorylation on the pLxIS motif by TBK1, recruits IRF3. Interacts with TBK1, TRAF6 and RIPK1 and these interactions are enhanced in the presence of WDFY1. Interacts with TRAFD1. Interacts with UBQLN1 (via UBA domain). Interacts with TLR4. Interacts with WDFY1 in response to poly(I:C). Interacts (via the TIR domain) with TLR3 in response to poly(I:C) and this interaction is enhanced in the presence of WDFY1. Interacts with TRIM56. Component of a multi-helicase-TICAM1 complex that acts as a cytoplasmic sensor of viral double-stranded RNA (dsRNA) and plays a role in the activation of a cascade of antiviral responses including the induction of pro-inflammatory cytokines. Interacts (via the TIR domain) with TLR5. Interacts with TRIM8. Interacts with TAX1BP1 and TRIM32; these interactions target TICAM1 to TAX1BP1-mediated selective autophagic degradation. Interacts with DDX50. (Microbial infection) Interacts with hepatitis C virus (HCV) NS3/4A protease; this interaction leads to TICAM1 cleavage, thereby disrupting TLR3 signaling and preventing the establishment of an antiviral state. (Microbial infection) Interacts with Seneca Valley virus protease 3C; this interaction allows the cleavage of TICAM1/TRIF and subsequent suppression of host innate immunity. (Microbial infection) Interacts (via C-terminus) with coxsackievirus B3 (CVB3) protease 3C.

Subcellular location. Cytoplasmic vesicle. Autophagosome. Cytoplasm. Cytosol. Mitochondrion.

Tissue specificity. Ubiquitously expressed but with higher levels in liver.

Post-translational modifications. Phosphorylated by TBK1. Following activation, phosphorylated by TBK1 at Ser-210 in the pLxIS motif. The phosphorylated pLxIS motif constitutes an IRF3-binding motif, leading to recruitment of the transcription factor IRF3 to induce type-I interferons and other cytokines. Polyubiquitinated at Lys-229 by TRIM38 with ‘Lys-48’-linked chains, leading to proteasomal degradation. Polyubiquitinated with ‘Lys-6’- and ‘Lys-33’-linked chains in a TRIM8-dependent manner; ubiquitination disrupts the interaction with TBK1 and subsequent interferon production. (Microbial infection) Cleaved and degraded by hepatitis A virus (HAV) protein 3CD allowing the virus to disrupt host TLR3 signaling. (Microbial infection) Cleaved by CVB3 protease 3C allowing the virus to disrupt host TLR3 signaling. (Microbial infection) Cleaved by Seneca Valley virus protease 3C allowing the virus to disrupt host TLR3 signaling. (Microbial infection) Cleaved by protease 3C of human enterovirus D68 (EV68) allowing the virus to disrupt host TLR3 signaling. (Microbial infection) Cleaved by HCV protease NS3/4A, thereby disrupting TLR3 signaling and preventing the establishment of an antiviral state.

Disease relevance. Encephalopathy, acute, infection-induced, 6, herpes-specific (IIAE6) [MIM:614850] A rare complication of human herpesvirus 1 (HHV-1) infection, occurring in only a small minority of HHV-1 infected individuals. It is characterized by hemorrhagic necrosis of parts of the temporal and frontal lobes. Onset is over several days and involves fever, headache, seizures, stupor, and often coma, frequently with a fatal outcome. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Domain organisation. The pLxIS motif constitutes an IRF3-binding motif: following phosphorylation by TBK1, the phosphorylated pLxIS motif of TICAM1 recruits IRF3. IRF3 is then phosphorylated and activated by TBK1 to induce type-I interferons and other cytokines. The N-terminal region is essential for activation of the IFNB promoter activity. The N-terminal domain (TRIF-NTD) is globular and consists of two alpha-helical subdomains connected by a 14-residue linker. It shares structural similarity with IFIT family members N-terminal regions.

RefSeq proteins (4): NP_001372607, NP_001372608, NP_001372609, NP_891549* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000157	TIR_dom	Domain
IPR017278	TICAM1	Family
IPR025735	RHIM	Binding_site
IPR035897	Toll_tir_struct_dom_sf	Homologous_superfamily
IPR040886	TRIF_N	Domain
IPR046946	TCAM1/2	Family

Pfam: PF12721, PF17798

UniProt features (97 total): sequence variant 21, mutagenesis site 19, helix 16, strand 8, site 7, compositionally biased region 5, region of interest 5, sequence conflict 5, short sequence motif 4, turn 3, chain 1, domain 1, modified residue 1, cross-link 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
3RC4	X-RAY DIFFRACTION	1.5
5JEL	X-RAY DIFFRACTION	1.6
4BSX	X-RAY DIFFRACTION	2.23
4C0M	X-RAY DIFFRACTION	2.8
9DK8	ELECTRON MICROSCOPY	3.3
8RLM	ELECTRON MICROSCOPY	3.5
2M1X	SOLUTION NMR
2M63	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IUC6-F1	63.88	0.24

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (7): 148 ((microbial infection) cleavage by cv3b); 159–160 ((microbial infection) cleavage; by viral seneca valley virus protease 3c); 190 ((microbial infection) cleavage; by viral hav 3cd); 312–313 ((microbial infection) cleavage; by viral ev68 protease c); 372–373 ((microbial infection) cleavage; by viral hcv ns3/4a); 554 ((microbial infection) cleavage; by viral hav 3cd); 653–654 ((microbial infection) cleavage; by viral ev68 protease c)

Post-translational modifications (2): 210, 229

Mutagenesis-validated functional residues (19):

Position	Phenotype
88	reduces binding to traf6 and activation of nfkb signaling pathway; when associated with a-252 and a-303.
159	complete loss of cleavage by seneca valley virus protease 3c.
190	no effect on cleavage by seneca valley virus protease 3c.
190	no cleavage by hav 3cd.
202	decreased interaction with irf3.
210–214	abolished ability to activate irf3.
210	abolished interaction with irf3.
252	loss of tcam1-induced nf-kappa-b activation. reduces interaction with traf6 and activation of nf-kappa-b signaling pathw
281	resistant to caspase cleavage, no effect on trim38-mediated degradation; when associated with e-289.
289	resistant to caspase cleavage, no effect on trim38-mediated degradation; when associated with e-281.
303	reduces binding to traf6 and activation of nfkb signaling pathway; when associated with a-88 and a-252.
372	complete loss of cleavage by hcv ns3/4a protease.
434	abolishes interaction with tlr3.
493	loss of tcam1-induced nf-kappa-b and irf3 activation.
554	no cleavage by hav 3cd.
653	complete loss of cleavage by cv3b; when associated with a-659; a-671 and a-702.
659	complete loss of cleavage by cv3b; when associated with a-653; a-671 and a-702.
672	complete loss of cleavage by cv3b; when associated with a-653; a-659 and a-702.
702	complete loss of cleavage by cv3b; when associated with a-653; a-659 and a-671.

Function

Pathways and Gene Ontology

Reactome pathways

34 pathways

ID	Pathway
R-HSA-140534	Caspase activation via Death Receptors in the presence of ligand
R-HSA-166166	MyD88-independent TLR4 cascade
R-HSA-168164	Toll Like Receptor 3 (TLR3) Cascade
R-HSA-168927	TICAM1, RIP1-mediated IKK complex recruitment
R-HSA-1810476	RIP-mediated NFkB activation via ZBP1
R-HSA-2562578	TRIF-mediated programmed cell death
R-HSA-5602566	TICAM1 deficiency - HSE
R-HSA-5602571	TRAF3 deficiency - HSE
R-HSA-9013957	TLR3-mediated TICAM1-dependent programmed cell death
R-HSA-9013973	TICAM1-dependent activation of IRF3/IRF7
R-HSA-9014325	TICAM1,TRAF6-dependent induction of TAK1 complex
R-HSA-936964	Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)
R-HSA-937041	IKK complex recruitment mediated by RIP1
R-HSA-937072	TRAF6-mediated induction of TAK1 complex within TLR4 complex
R-HSA-975163	IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation
R-HSA-9824878	Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7
R-HSA-9828211	Regulation of TBK1, IKKε-mediated activation of IRF3, IRF7 upon TLR3 ligation
R-HSA-109581	Apoptosis
R-HSA-1606322	ZBP1(DAI) mediated induction of type I IFNs
R-HSA-1643685	Disease
R-HSA-166016	Toll Like Receptor 4 (TLR4) Cascade
R-HSA-168138	Toll Like Receptor 9 (TLR9) Cascade
R-HSA-168181	Toll Like Receptor 7/8 (TLR7/8) Cascade
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-168898	Toll-like Receptor Cascades
R-HSA-1834949	Cytosolic sensors of pathogen-associated DNA
R-HSA-5260271	Diseases of Immune System
R-HSA-5357769	Caspase activation via extrinsic apoptotic signalling pathway
R-HSA-5357801	Programmed Cell Death

MSigDB gene sets: 331 (showing top): REACTOME_TRAF6_MEDIATED_INDUCTION_OF_TAK1_COMPLEX_WITHIN_TLR4_COMPLEX, REACTOME_IKK_COMPLEX_RECRUITMENT_MEDIATED_BY_RIP1, GOBP_CELLULAR_RESPONSE_TO_LIPOPROTEIN_PARTICLE_STIMULUS, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_REGULATION_OF_AUTOPHAGY, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, GOBP_INFLAMMATORY_RESPONSE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_B_CELL_ACTIVATION, GOBP_MACROPHAGE_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION_INVOLVED_IN_IMMUNE_RESPONSE

GO Biological Process (39): toll-like receptor signaling pathway (GO:0002224), macrophage activation involved in immune response (GO:0002281), positive regulation of myeloid dendritic cell cytokine production (GO:0002735), nitric oxide biosynthetic process (GO:0006809), inflammatory response (GO:0006954), positive regulation of autophagy (GO:0010508), positive regulation of gene expression (GO:0010628), positive regulation of B cell proliferation (GO:0030890), positive regulation of protein ubiquitination (GO:0031398), lipopolysaccharide-mediated signaling pathway (GO:0031663), positive regulation of type I interferon production (GO:0032481), positive regulation of chemokine production (GO:0032722), positive regulation of interferon-beta production (GO:0032728), positive regulation of interleukin-6 production (GO:0032755), positive regulation of tumor necrosis factor production (GO:0032760), positive regulation of natural killer cell activation (GO:0032816), toll-like receptor 3 signaling pathway (GO:0034138), toll-like receptor 4 signaling pathway (GO:0034142), TRIF-dependent toll-like receptor signaling pathway (GO:0035666), B cell proliferation (GO:0042100), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), regulation of protein-containing complex assembly (GO:0043254), response to exogenous dsRNA (GO:0043330), innate immune response (GO:0045087), positive regulation of nitric oxide biosynthetic process (GO:0045429), defense response to virus (GO:0051607), positive regulation of macrophage cytokine production (GO:0060907), cellular response to lipopolysaccharide (GO:0071222), apoptotic signaling pathway (GO:0097190), cellular response to oxidised low-density lipoprotein particle stimulus (GO:0140052), positive regulation of cytokine production involved in inflammatory response (GO:1900017), immune system process (GO:0002376), MyD88-independent toll-like receptor signaling pathway (GO:0002756), apoptotic process (GO:0006915), signal transduction (GO:0007165), cell surface receptor signaling pathway (GO:0007166), response to lipopolysaccharide (GO:0032496), B cell activation (GO:0042113), positive regulation of B cell activation (GO:0050871)

GO Molecular Function (4): protein kinase binding (GO:0019901), signaling adaptor activity (GO:0035591), molecular adaptor activity (GO:0060090), protein binding (GO:0005515)

GO Cellular Component (9): mitochondrion (GO:0005739), endosome (GO:0005768), early endosome (GO:0005769), autophagosome (GO:0005776), cytosol (GO:0005829), endosome membrane (GO:0010008), ripoptosome (GO:0097342), cytoplasm (GO:0005737), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Toll Like Receptor 3 (TLR3) Cascade	4
TRIF (TICAM1)-mediated TLR4 signaling	4
Diseases associated with the TLR signaling cascade	2
Caspase activation via extrinsic apoptotic signalling pathway	1
Toll Like Receptor 4 (TLR4) Cascade	1
Toll-like Receptor Cascades	1
ZBP1(DAI) mediated induction of type I IFNs	1
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	1
Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)	1
TICAM1-dependent activation of IRF3/IRF7	1
Programmed Cell Death	1
Cytosolic sensors of pathogen-associated DNA	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of cytokine production	3
cytoplasm	3
binding	2
endosome	2
cellular anatomical structure	2
pattern recognition receptor signaling pathway	1
myeloid cell activation involved in immune response	1
leukocyte activation involved in immune response	1
immune response	1
macrophage activation	1
myeloid dendritic cell cytokine production	1
positive regulation of dendritic cell cytokine production	1
regulation of myeloid dendritic cell cytokine production	1
positive regulation of myeloid leukocyte mediated immunity	1
positive regulation of myeloid leukocyte cytokine production involved in immune response	1
biosynthetic process	1
nitric oxide metabolic process	1
defense response	1
autophagy	1
positive regulation of catabolic process	1
regulation of autophagy	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
regulation of B cell proliferation	1
B cell proliferation	1
positive regulation of lymphocyte proliferation	1
positive regulation of B cell activation	1
protein ubiquitination	1
regulation of protein ubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
cell surface receptor signaling pathway	1
cellular response to lipopolysaccharide	1
regulation of type I interferon production	1
type I interferon production	1
chemokine production	1
regulation of chemokine production	1
positive regulation of type I interferon production	1
interferon-beta production	1
regulation of interferon-beta production	1

Protein interactions and networks

STRING

1907 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TICAM1	TLR3	O15455	997
TICAM1	TLR4	O00206	991
TICAM1	MYD88	P78397	919
TICAM1	SARM1	Q6SZW1	914
TICAM1	TIRAP	P58753	907
TICAM1	IRF3	Q14653	857
TICAM1	RIGI	O95786	855
TICAM1	IFIH1	Q9BYX4	836
TICAM1	MAVS	Q7Z434	821
TICAM1	TRAF6	Q9Y4K3	815
TICAM1	IFNB1	P01574	814
TICAM1	IKBKE	Q14164	808
TICAM1	TRAF3	Q13114	768
TICAM1	RIPK1	Q13546	768
TICAM1	IRF7	Q92985	768

IntAct

21 interactions, top by confidence:

A	B	Type	Score
TICAM1	TBK1	psi-mi:“MI:0915”(physical association)	0.690
TBK1		psi-mi:“MI:0915”(physical association)	0.570
TICAM1	CARM1	psi-mi:“MI:0915”(physical association)	0.500
SARM1	TICAM1	psi-mi:“MI:0407”(direct interaction)	0.440
TICAM1	CARM1	psi-mi:“MI:0915”(physical association)	0.400
TICAM1	TRIM56	psi-mi:“MI:0915”(physical association)	0.400
TICAM2	TICAM1	psi-mi:“MI:0915”(physical association)	0.400
PIAS4	TICAM1	psi-mi:“MI:0915”(physical association)	0.400
TICAM1	TNFAIP3	psi-mi:“MI:0915”(physical association)	0.400
TICAM1	SRSF4	psi-mi:“MI:0915”(physical association)	0.370
CEP170P1	PCYT1A	psi-mi:“MI:0914”(association)	0.350
CDCA5	BDP1	psi-mi:“MI:0914”(association)	0.350
Immt	GOSR1	psi-mi:“MI:0914”(association)	0.350
KIF21B		psi-mi:“MI:0914”(association)	0.350
MKNK2	WWP2	psi-mi:“MI:0914”(association)	0.350
MKNK2	WDR46	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
TICAM1	INPPL1	psi-mi:“MI:0914”(association)	0.350
TICAM1	TANK	psi-mi:“MI:0914”(association)	0.350

BioGRID (110): TICAM1 (Affinity Capture-Western), TICAM1 (Affinity Capture-Western), CARM1 (Affinity Capture-MS), TRAF6 (Reconstituted Complex), TICAM1 (Affinity Capture-Western), TICAM1 (Affinity Capture-MS), TICAM1 (Affinity Capture-MS), TICAM1 (Affinity Capture-MS), TICAM1 (Affinity Capture-MS), TICAM1 (Affinity Capture-MS), TICAM1 (Affinity Capture-MS), TICAM1 (Affinity Capture-Western), RIPK1 (Affinity Capture-Western), TRAF6 (Affinity Capture-Western), TBK1 (Affinity Capture-Western)

ESM2 similar proteins: A0JPN4, A2A288, A2ARK0, A6ND36, A6QQJ8, A7E316, E9Q0S6, E9Q2Z1, O15037, O54714, O54967, O70260, O70405, O75385, O94983, P42335, P48778, Q07912, Q0P4K8, Q17R13, Q1LVK9, Q32PJ7, Q4V8I3, Q5D1E7, Q5D1E8, Q5DTV4, Q5HYM0, Q5JV73, Q5SWY7, Q5SXM2, Q5U2X5, Q5XIS1, Q68CZ2, Q6A037, Q6IRU7, Q6P1H6, Q6S5L8, Q7TP65, Q7TSG2, Q80U38

Diamond homologs: Q2LGB7, Q4JF29, Q80UF7, Q86XR7, Q8BJQ4, Q8IUC6

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
TICAM2	“up-regulates activity”	TICAM1	binding
TICAM1	“up-regulates activity”	TBK1	binding
TICAM1	“up-regulates activity”	RIPK1	binding
TRAF2	up-regulates	TICAM1	polyubiquitination
TRAF6	up-regulates	TICAM1	polyubiquitination
RNF216	“down-regulates quantity by destabilization”	TICAM1	ubiquitination
TLR4	“up-regulates activity”	TICAM1	binding
SARM1	down-regulates	TICAM1	binding
TLRs	“up-regulates activity”	TICAM1	binding
DDX21	“up-regulates activity”	TICAM1	binding
TLR2	“up-regulates activity”	TICAM1	binding
TLR9	“up-regulates activity”	TICAM1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	239
Likely benign	184
Benign	11

Top pathogenic / likely-pathogenic (0)

SpliceAI

241 predictions. Top by Δscore:

Variant	Effect	Δscore
19:4818517:C:CC	acceptor_gain	0.9900
19:4831610:CTA:C	donor_loss	0.9900
19:4831611:TA:T	donor_loss	0.9900
19:4831612:A:AC	donor_gain	0.9900
19:4831612:ACCAG:A	donor_loss	0.9900
19:4831613:C:CC	donor_gain	0.9900
19:4818512:CAGAT:C	acceptor_gain	0.9800
19:4818516:TC:T	acceptor_loss	0.9800
19:4818517:C:CA	acceptor_loss	0.9800
19:4818514:GAT:G	acceptor_gain	0.9700
19:4829424:TCC:T	donor_gain	0.9600
19:4818515:AT:A	acceptor_gain	0.9400
19:4831611:TAC:T	donor_gain	0.9400
19:4829417:TGC:T	donor_gain	0.9300
19:4831612:A:AG	donor_gain	0.9300
19:4831613:C:G	donor_gain	0.9200
19:4818519:G:C	acceptor_gain	0.9100
19:4820338:TGA:T	donor_gain	0.9100
19:4831612:AC:A	donor_gain	0.9100
19:4831613:CC:C	donor_gain	0.9100
19:4829419:C:CT	donor_gain	0.9000
19:4818513:AGAT:A	acceptor_gain	0.8900
19:4829425:CC:C	donor_gain	0.8900
19:4831613:CCA:C	donor_gain	0.8800
19:4818527:C:CT	acceptor_gain	0.8500
19:4831614:C:G	donor_gain	0.8400
19:4818519:G:GC	acceptor_gain	0.8300
19:4820274:G:C	donor_gain	0.8100
19:4831604:C:CA	donor_gain	0.7900
19:4816610:C:CT	donor_gain	0.7800

AlphaMissense

4593 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:4817187:A:C	F397L	0.994
19:4817187:A:T	F397L	0.994
19:4817189:A:G	F397L	0.994
19:4816336:A:G	I681T	0.993
19:4817085:G:C	F431L	0.992
19:4817085:G:T	F431L	0.992
19:4817087:A:G	F431L	0.992
19:4816795:A:G	F528S	0.991
19:4817152:G:T	A409D	0.991
19:4817188:A:G	F397S	0.991
19:4816336:A:T	I681N	0.990
19:4817086:A:G	F431S	0.990
19:4817105:C:G	A425P	0.990
19:4817196:G:C	F394L	0.990
19:4817196:G:T	F394L	0.990
19:4817198:A:G	F394L	0.990
19:4816336:A:C	I681S	0.988
19:4817025:G:C	F451L	0.987
19:4817025:G:T	F451L	0.987
19:4817027:A:G	F451L	0.987
19:4817140:C:G	R413P	0.987
19:4816818:G:C	F520L	0.986
19:4816818:G:T	F520L	0.986
19:4816820:A:G	F520L	0.986
19:4817131:A:G	L416P	0.986
19:4817045:C:G	A445P	0.984
19:4816794:G:C	F528L	0.983
19:4816794:G:T	F528L	0.983
19:4816796:A:G	F528L	0.983
19:4817143:A:T	V412D	0.983

dbSNP variants (sampled 300 via entrez): RS1000091105 (19:4827805 G>C,T), RS1000127244 (19:4829010 A>G,T), RS1000563342 (19:4831927 C>T), RS1000635489 (19:4831728 C>G), RS1000756204 (19:4832406 T>A), RS1000946030 (19:4828362 A>G), RS1000946996 (19:4822858 G>A), RS1001251384 (19:4823999 A>C), RS1001388611 (19:4824253 C>T), RS1001441763 (19:4823072 C>A,G), RS1001797552 (19:4826319 T>A,G), RS1001974590 (19:4819188 C>A,T), RS1002098587 (19:4825346 G>A), RS1002164935 (19:4826449 C>A,T), RS1002531405 (19:4825141 G>A)

Disease associations

OMIM: gene MIM:607601 | disease phenotypes: MIM:614850

GenCC curated gene-disease

Disease	Classification	Inheritance
herpes simplex encephalitis, susceptibility to, 4	Strong	Autosomal recessive

Mondo (1): herpes simplex encephalitis, susceptibility to, 4 (MONDO:0013921)

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

HPO phenotypes

36 total (30 of 36 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0001250	Seizure
HP:0001259	Coma
HP:0001262	Excessive daytime somnolence
HP:0001347	Hyperreflexia
HP:0001945	Fever
HP:0001974	Increased total leukocyte count
HP:0002017	Nausea and vomiting
HP:0002133	Status epilepticus
HP:0002167	Abnormal speech pattern
HP:0002181	Cerebral edema
HP:0002315	Headache
HP:0002349	Focal aware seizure
HP:0002353	EEG abnormality
HP:0002384	Focal impaired awareness seizure
HP:0002721	Immunodeficiency
HP:0002902	Hyponatremia
HP:0002922	Increased CSF protein concentration
HP:0003829	Typified by incomplete penetrance
HP:0004302	Functional motor deficit
HP:0004372	Reduced consciousness
HP:0004887	Respiratory failure requiring assisted ventilation
HP:0007185	Loss of consciousness
HP:0011107	Recurrent aphthous stomatitis
HP:0011227	Elevated circulating C-reactive protein concentration
HP:0011463	Childhood onset
HP:0011897	Increased total neutrophil count
HP:0011972	Hypoglycorrhachia
HP:0012302	Herpes simplex encephalitis

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001509_5	Vitiligo	9.000000e-08
GCST004785_19	Vitiligo	2.000000e-14
GCST007932_34	Medication use (thyroid preparations)	2.000000e-17
GCST90013410_60	Basal cell carcinoma	1.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009933	Thyroid preparation use measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Resveratrol	affects cotreatment, decreases expression, decreases reaction, increases expression	2
Estradiol	increases expression	2
Plant Extracts	decreases reaction, increases expression, affects cotreatment, decreases expression	2
Silicon Dioxide	increases expression	2
Tobacco Smoke Pollution	increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
dicrotophos	increases expression	1
bisphenol A	affects cotreatment, increases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	affects splicing, increases expression	1
ochratoxin A	decreases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
lipopolysaccharide, E. coli O26-B6	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
abrine	increases expression	1
3,5-bis(2-fluorobenzylidene)piperidin-4-one	increases expression, decreases reaction	1
Aripiprazole	increases expression, affects cotreatment	1
Chelating Agents	affects binding, increases expression	1
Copper	affects binding, increases expression	1
Curcumin	decreases reaction, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Diethylhexyl Phthalate	increases expression	1
Doxorubicin	decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Methotrexate	increases expression	1
Nickel	increases expression	1
Oxygen	decreases reaction, increases expression	1

Cellosaurus cell lines

8 cell lines: 7 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A8AM	THP1-Dual KO-TRIF	Cancer cell line	Male
CVCL_D8CG	Ubigene A-549 TICAM1 KO	Cancer cell line	Male
CVCL_D8X4	Ubigene HCT 116 TICAM1 KO	Cancer cell line	Male
CVCL_D9U9	Ubigene HEK293 TICAM1 KO	Transformed cell line	Female
CVCL_E0R0	Ubigene HeLa TICAM1 KO	Cancer cell line	Female
CVCL_E9DI	Abcam U-87MG TICAM1 KO	Cancer cell line	Male
CVCL_TS32	HAP1 TICAM1 (-) 1	Cancer cell line	Male
CVCL_TS33	HAP1 TICAM1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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