Alternative titles; symbols
HGNC Approved Gene Symbol: TICAM1
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38) : 19:4,815,932-4,831,712 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.3 | {Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 6} | 614850 | Autosomal dominant; Autosomal recessive | 3 |
TRIF, or TICAM1, is a Toll/IL1R (147810) (TIR) domain-containing adaptor molecule, like MYD88 (602170) and TIRAP (606252), that induces interferon-beta (IFNB; 147640), specifically interacts with TLR3 (603029), and activates nuclear factor kappa-B (NFKB; see 164011) (Yamamoto et al., 2002).
By EST database searching for sequences containing TIR domains, followed by probing cell lines, Yamamoto et al. (2002) obtained a full-length cDNA encoding TRIF. The predicted 712-amino acid protein is 48% identical to the mouse protein. TRIF has a TIR domain, which contains a conserved proline essential for TLR activation, on its C-terminal side. Northern blot analysis revealed ubiquitous expression that was strongest in liver.
Because dominant-negative MYD88 or TIRAP were unable to block TLR3-mediated IFNB activation by double-stranded (ds)RNA, Oshiumi et al. (2003) used a yeast 2-hybrid system and identified TRIF, which they termed TICAM1, as a TLR3-interacting protein. They obtained the full-length cDNA by EST database searching and RT-PCR. TICAM1 contains proline-rich N and C termini, as well as a TIR motif that does not interact with TLR2 or TLR4. The TIR domain of TICAM1 lacks conserved (F/Y)D, RD, and FW motifs, and TICAM1 lacks a death domain. By RT-PCR analysis, Oshiumi et al. (2003) detected a 2.6-kb TICAM1 transcript in all tissues and cell types tested.
By genomic sequence analysis, Oshiumi et al. (2003) mapped the TICAM1 gene to chromosome 19p13.3.
Yamamoto et al. (2002) showed that ectopic expression of TRIF induced NFKB activation, which was dependent on both the N- and C-terminal portions of TRIF, and strongly induced the IFNB promoter, which was dependent on the presence of both the N terminus and the TIR domain of TRIF, but not the remainder of the C terminus. Functional analysis indicated that TRIF is involved in signaling pathways of multiple TLRs downstream of MYD88 and TIRAP. Dominant-negative TRIF abolished TLR3 signaling and blocked activity mediated by TLR2 (603028), TLR4 (603030), and TLR7 (300365). Coimmunoprecipitation analysis showed that TRIF interacts with TLR2, TLR3, and IRF3 (603734). The authors concluded that TRIF appears to be involved in MYD88-independent activation of TLR3 signaling.
By coimmunoprecipitation analysis, Oshiumi et al. (2003) showed that TICAM1 interacts specifically with TLR3, but not with other TLRs. Functional analysis showed that the association of TLR3 and TICAM1 mediates dsRNA activation of IFNB, through either NFKB, AP1 (see 165160), or IRF3. TICAM1 activation of NFKB was found to occur predominantly through IRAK1 (300283) rather than IRAK2 (603304). Small interfering (si)RNA blockage of TICAM1, just upstream of the TIR domain, reduced IFNB production in response to dsRNA.
Meylan et al. (2004) noted that TRIF is necessary for TLR3-dependent activation of NFKB. They showed that the C-terminal RIP homotypic interaction motif (RHIM) of TRIF recruits RIP1 (RIPK1; 603453) and RIP3 (RIPK3; 605817) via their intermediary domains. Overexpression of RIP3 resulted in dose-dependent inhibition of TRIF-induced NFKB activation. Coimmunoprecipitation and RT-PCR analysis indicated that TRIF serves as an adaptor protein linking RIP1 and TLR3 and that RIP1 mediates TLR3-induced NFKB activation. Meylan et al. (2004) concluded that RIP1 is important not only in later phases of the immune response, when TNF is active, but also at the beginning, when an antiviral immune response is engaged via TLR3 interaction with double-stranded RNA.
Carty et al. (2006) found that expression of TRIF in macrophages led to activation of NFKB and IRF3, whereas expression of SARM had little or no effect. Increased SARM expression inhibited production of CCL5 (187011) and IRF7 (605047) after TLR3 or TLR4 activation, but not after TLR9 (605474) activation, indicating that SARM blocked TRIF-dependent, but not MYD88-dependent, gene expression. Immunoprecipitation and yeast 2-hybrid analysis showed that SARM and TRIF interacted, and mutation analysis revealed that inhibition of TRIF by SARM required the sterile alpha motif and TIR domains of SARM. RNA-mediated interference of SARM blocked its ability to inhibit TRIF.
By immunoprecipitation and protein pull-down analyses using biotinylated poly I:C, Zhang et al. (2011) identified a cytosolic, endosome-independent sensor of viral nucleotides consisting of the RNA helicases Ddx1 (601257), Ddx21 (606357), and Dhx36 (612767) and the adaptor molecule Trif in mouse myeloid dendritic cells (mDCs). The dsRNA sensors Pkr (EIF2AK2; 176871) and Lgp2 (DHX58; 608588) were also precipitated. Knockdown of each helicase via short hairpin RNA blocked the ability of mDCs to mount type I interferon and cytokine responses to poly I:C, influenza A, and reovirus. Ddx1 bound poly I:C through its helicase A domain, while Dhx36 and Ddx21 bound the TIR domain of Trif via their HA2-DUF and PRK domains, respectively. Zhang et al. (2011) concluded that the DDX1-DDX21-DHX36 complex is a dsRNA sensor that uses the TRIF pathway to activate type I interferon responses in the cytosol of mDCs.
Using mouse strains lacking genes involved in inflammasome activation, Rathinam et al. (2012) showed that endotoxin of Gram-negative bacteria interacted with Tlr4, followed by interaction of this complex with Trif, expression of and signaling by Ifnb, and ultimately expression of Casp11 (see CASP4; 602664). Casp11 then worked together with the assembled Nlrp3 (606416) inflammasome to activate Casp1 (147678), leading to Il1b (147720) and Il18 (600953) secretion and Casp1-independent cell death. This pathway was not engaged by Gram-positive bacteria. Rathinam et al. (2012) concluded that TLRs are master regulators of inflammasome signaling, particularly during Gram-negative bacterial infection-induced septic shock.
Using biochemical and mouse cell- and human cell-based assays, Liu et al. (2015) found that both MAVS (609676) and STING (612374) interacted with IRF3 (603734) in a phosphorylation-dependent manner. The authors showed that both MAVS and STING are phosphorylated in response to stimulation at their respective C-terminal pLxIS consensus motif (p, hydrophilic residue; x, any residue; S, phosphorylation site). This phosphorylation event then recruits IRF3 to the active adaptor protein and is essential for IRF3 activation. Point mutations that impair the phosphorylation of MAVS or STING at their consensus motif abrogated IRF3 binding and subsequent interferon (see 147660) induction. Liu et al. (2015) found that MAVS is phosphorylated by the kinases TBK1 (604834) and IKK (see 600664), whereas STING is phosphorylated by TBK1. Phosphorylated MAVS and STING subsequently bind to conserved, positively charged surfaces of IRF3, thereby recruiting IRF3 for its phosphorylation and activation by TBK1. Liu et al. (2015) also showed that TRIF-mediated activation of IRF3 depends of TRIF phosphorylation at the pLxIS motif commonly found in MAVS, STING, and IRF3. The authors concluded that phosphorylation of innate immune adaptor proteins is an essential and conserved mechanism that selectively recruits IRF3 to activate type I interferon production.
Sancho-Shimizu et al. (2011) identified causative mutations in the TRIF gene in 2 unrelated patients with herpes simplex encephalitis (HSE) (IIAE6; 614850). The first patient, a Saudi Arabian boy with autosomal recessive HSE susceptibility, had a homozygous nonsense mutation (R141X; 607601.0001) that resulted in premature termination and no detectable TRIF protein. The second patient, a European girl of mixed European descent with autosomal dominant HSE susceptibility, was heterozygous for a ser186-to-leu (S186L; 607601.0002) substitution in the N terminus of the protein. Investigations of patient dermal fibroblasts revealed that the R141X and S186L mutations resulted in impaired production of IFNB, IFNL1 (IL29; 607403), IFNL3 (IL28B; 607402), and IL6 (147620) after stimulation with poly(I:C), a TLR3 agonist. Overall, the TRIF deficiency was partial in the patient heterozygous for S186L, whereas it was complete in the patient homozygous for R141X. The TRIF-dependent TLR4-signaling pathway was also abolished in cells from the patient homozygous for R141X, whereas it was unaffected in cells from the patient heterozygous for S186L. Responses to viruses were impaired in both patients. Sancho-Shimizu et al. (2011) also reported a third patient, an Iranian boy who presented with HSE at age 4.5 years, who was heterozygous for a pro625-to-leu (P625L) missense mutation in the C terminus of TRIF. However, unlike the other TRIF mutations, P625L showed no deleterious effects in cellular assays and was considered nonpathogenic.
In 2 unrelated Danish men (P5 and P6) with onset of herpes simplex encephalitis after age 60 years, Mork et al. (2015) identified heterozygous missense mutations in the TICAM1 gene (A568T, 607601.0003 and S160F, 607601.0004). The mutations were found by whole-exome sequencing of a cohort of 16 patients with adult-onset HSE and confirmed by Sanger sequencing. One patient was infected with HSV-1 and the other with HSV-2. Peripheral blood mononuclear cells from both patients showed variable but significantly impaired beta-interferon (IFNB1; 147640), CXCL10 (147310), and/or TNFA (191160) responses to poly(I;C) stimulation and/or HSV-1 infection compared to controls. The findings suggested that TICAM1 variants may also contribute to HSE susceptibility in adults.
Using ENU mutagenesis, Hoebe et al. (2003) introduced a germline mutation called Lps2, which abolishes cytokine responses to double-stranded mRNA and severely impairs responses to the endotoxin lipopolysaccharide (LPS), suggesting that TLR3 and TLR4 (603030) might share a specific, proximal transducer. Hoebe et al. (2003) identified the Lps2 mutation: a distal frameshift error in a Toll/interleukin-1 receptor/resistance (TIR) adaptor protein known as Trif or Ticam1. Trif(Lps2) homozygotes are markedly resistant to the toxic effects of LPS, and are hypersusceptible to mouse cytomegalovirus, failing to produce type 1 interferons when infected. Compound homozygosity for mutations at Trif and MyD88 (602170) loci ablated all responses to LPS, indicating that only 2 signaling pathways emanate from the LPS receptor. However, Hoebe et al. (2003) found that a Trif-independent cell population was detectable when Trif(Lps2) mutant macrophages were stimulated with LPS. This revealed that an alternative MyD88-dependent 'adaptor X' pathway is present in some, but not all, macrophages, and implies afferent immune specialization. (Homozygosity for 2 mutations at separate loci should perhaps be referred to as double homozygosity, reserving the term compound homozygosity for mutations at 2 different sites in a single gene.)
Yamamoto et al. (2003) created Trif-deficient mice by targeted disruption. Trif-deficient mice were defective in both Tlr3- and Tlr4-mediated expression of Ifnb and activation of Irf3. Furthermore, inflammatory cytokine production in response to Tlr4 ligand, but not to other TLR ligands, was severely impaired in Trif-deficient macrophages. Mice deficient in both Myd88 and Trif showed complete loss of Nfkb activation in response to Tlr4 stimulation. Yamamoto et al. (2003) concluded that TRIF is essential for TLR3- and TLR4-mediated signaling pathways facilitating mammalian antiviral host defense.
Mice genetically deficient in both Myd88 and Trif have a complete lack of known Toll-like receptor signaling, thus allowing assessment of Toll-like receptor dependence of antibody responses. Gavin et al. (2006) used these double knockouts to investigate the role of Toll-like receptor signaling in antibody responses to immunization and the augmenting roles of 4 typical adjuvants (alum, Freund complete adjuvant, Freund incomplete adjuvant, and monophosphoryl-lipid A/trehalose dicorynomycolate adjuvant) to that response. Regardless of adjuvant, these mice exhibited robust antibody responses. Gavin et al. (2006) concluded that Toll-like receptor signaling does not account for the action of classical adjuvants and does not fully explain the action of strong adjuvant containing a Toll-like receptor ligand.
Riad et al. (2011) found that Trif -/- mice infected with coxsackie group B serotype-3 (CVB3) had increased cardiac remodeling, severe heart failure, and 100% mortality, whereas CVB3-infected wildtype mice had only mild myocarditis. Trif -/- mice have reduced virus control in cardiac tissue and myocytes and dynamic cardiac cytokine activation, including suppressed production of Ifnb in early viremia. Trif -/- myocytes displayed a Tlr4-dependent suppression of Ifnb. Pharmacologic treatment of CVB3-infected Trif -/- mice with Ifnb improved virus control and reduced cardiac inflammation, and treatment during the viremic phase resulted in reduced mortality. Riad et al. (2011) concluded that TRIF is essential for the control of CVB3 in heart.
In a Saudi Arabian boy, born of first-cousin parents, who developed herpes simplex encephalitis (IIAE6; 614850) at age 2 years, Sancho-Shimizu et al. (2011) identified a homozygous 421C-T transition in the TRIF gene, resulting in a premature termination codon, arg141 to ter (R141X), in the N terminus of TRIF. At age 3.5 years, the patient had no other severe infectious diseases, but he suffered neurologic sequelae, principally delayed speech and recurrent herpetic stomatitis.
In a girl of French, Portuguese, and Swiss descent who presented with herpes simplex encephalitis (IIAE6; 614850) at age 21 months, Sancho-Shimizu et al. (2011) identified a heterozygous 557C-T transition in the TRIF gene, resulting in a ser186-to-leu (S186L) substitution in the N terminus of the protein. After 4 days of acyclovir treatment, the patient had no relapse, and she had no history of herpes labialis, but she was blind and epileptic. At age 18 years, the patient had no other severe infectious diseases and had serologic evidence of exposure to other herpesviruses. The patient's mother and grandfather had the same mutation and antibodies to HSV-1, but they had no history of HSE.
In a man (P5) with onset of herpes simplex encephalitis (IIAE6; 614850) due to HSV-1 at age 73, Mork et al. (2015) identified a heterozygous c.1702G-A transition (c.1702G-A, NM_182919.3) in the TICAM1 gene, resulting in an ala568-to-thr (A568T) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present at a low frequency (0.0031) in the ExAC database. The patient had no other severe viral infections. Patient peripheral blood mononuclear cells showed significantly impaired antiviral responses when stimulated with HSV-1, suggesting a loss-of-function effect.
In a man (P6) with onset of herpes simplex encephalitis (IIAE6; 614850) due to HSV-2 at age 69, Mork et al. (2015) identified a heterozygous c.749C-T transition (c.749C-T, NM_182919.3) in the TICAM1 gene, resulting in a ser160-to-phe (S160F) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was found at a low frequency (0.0024) in the ExAC database. Patient peripheral blood mononuclear cells showed significantly impaired antiviral responses to poly(I:C) stimulation and weak interferon response after HSV-1 infection, suggesting a loss-of-function effect. The patient experienced a severe genital herpes eruption due to HSV-2 a few days prior to the HSE episode.
Carty, M., Goodbody, R., Schroder, M., Stack, J., Moynagh, P. N., Bowie, A. G. The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling. Nature Immun. 7: 1074-1081, 2006. [PubMed: 16964262] [Full Text: https://doi.org/10.1038/ni1382]
Gavin, A. L., Hoebe, K., Duong, B., Ota, T., Martin, C., Beutler, B., Nemazee, D. Adjuvant-enhanced antibody responses in the absence of Toll-like receptor signaling. Science 314: 1936-1938, 2006. [PubMed: 17185603] [Full Text: https://doi.org/10.1126/science.1135299]
Hoebe, K., Du, X., Georgel, P., Janssen, E., Tabeta, K., Kim, S. O., Goode, J., Lin, P., Mann, N., Mudd, S., Crozat, K., Sovath, S., Han, J., Beutler, B. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424: 743-748, 2003. [PubMed: 12872135] [Full Text: https://doi.org/10.1038/nature01889]
Liu, S., Cai, X., Wu, J., Cong, Q., Chen, X., Li, T., Du, F., Ren, J., Wu, Y.-T., Grishin, N. V., Chen, Z. J. Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science 347: aaa2630, 2015. Note: Electronic Article. [PubMed: 25636800] [Full Text: https://doi.org/10.1126/science.aaa2630]
Meylan, E., Burns, K., Hofmann, K., Blancheteau, V., Martinon, F., Kelliher, M., Tschopp, J. RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa-B activation. Nature Immun. 5: 503-507, 2004. [PubMed: 15064760] [Full Text: https://doi.org/10.1038/ni1061]
Mork, N., Kofod-Olsen, E., Sorensen, K. B., Bach, E., Orntoft, T. F., Ostergaard, L., Paludan, S. R., Christiansen, M., Mogensen, T. H. Mutations in the TLR3 signaling pathway and beyond in adult patients with herpes simplex encephalitis. Genes Immun. 16: 552-566, 2015. [PubMed: 26513235] [Full Text: https://doi.org/10.1038/gene.2015.46]
Oshiumi, H., Matsumoto, M., Funami, K., Akazawa, T., Seya, T. TICAM-I, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-beta induction. Nature Immun. 4: 161-167, 2003. [PubMed: 12539043] [Full Text: https://doi.org/10.1038/ni886]
Rathinam, V. A. K., Vanaja, S. K., Waggoner, L., Sokolovska, A., Becker, C., Stuart, L. M., Leong, J. M., Fitzgerald, K. A. TRIF licenses caspase-11-dependent NLRP3 inflammasome activation by gram-negative bacteria. Cell 150: 606-619, 2012. [PubMed: 22819539] [Full Text: https://doi.org/10.1016/j.cell.2012.07.007]
Riad, A., Westermann, D., Zietsch, C., Savvatis, K., Becher, P. M., Bereswill, S., Heimesaat, M. M., Lettau, O., Lassner, D., Dorner, A., Poller, W., Busch, M., Felix, S. B., Schultheiss, H. P., Tschope, C. TRIF is a critical survival factor in viral cardiomyopathy. J. Immun. 186: 2561-2570, 2011. [PubMed: 21239721] [Full Text: https://doi.org/10.4049/jimmunol.1002029]
Sancho-Shimizu, V., Perez de Diego, R., Lorenzo, L., Halwani, R., Alangari, A., Israelsson, E., Fabrega, S., Cardon, A., Maluenda, J., Tatematsu, M., Mahvelati, F., Herman, M. {and 22 others}: Herpes simplex encephalitis in children with autosomal recessive and dominant TRIF deficiency. J. Clin. Invest. 121: 4889-4902, 2011. [PubMed: 22105173] [Full Text: https://doi.org/10.1172/JCI59259]
Yamamoto, M., Sato, S., Hemmi, H., Hoshino, K., Kaisho, T., Sanjo, H., Takeuchi, O., Sugiyama, M., Okabe, M., Takeda, K., Akira, S. Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science 301: 640-642, 2003. [PubMed: 12855817] [Full Text: https://doi.org/10.1126/science.1087262]
Yamamoto, M., Sato, S., Mori, K., Hoshino, K., Takeuchi, O., Takeda, K., Akira, S. Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling. J. Immun. 169: 6668-6672, 2002. [PubMed: 12471095] [Full Text: https://doi.org/10.4049/jimmunol.169.12.6668]
Zhang, Z., Kim, T., Bao, M., Facchinetti, V., Jung, S. Y., Ghaffari, A. A., Qin, J., Cheng, G., Liu, Y.-J. DDX1, DDX21, and DHX36 helicases form a complex with the adaptor molecule TRIF to sense dsRNA in dendritic cells. Immunity 34: 866-878, 2011. [PubMed: 21703541] [Full Text: https://doi.org/10.1016/j.immuni.2011.03.027]