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Gene Review

TIRAP  -  toll-interleukin 1 receptor (TIR) domain...

Homo sapiens

Synonyms: Adaptor protein Wyatt, BACTS1, MAL, Mal, MyD88 adapter-like protein, ...
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Disease relevance of TIRAP

  • Together these results underscore the importance of Rac1 and TIRAP in TLR4 activation of HIV replication and help delineate the signaling pathways induced by TLRs to mediate microbial Ag-induced HIV replication and HIV pathogenesis [1].
  • Furthermore, immune responses in the lungs of TIRAP-/- mice were attenuated against E. coli compared with TIRAP+/+ mice [2].
  • Differences between signals generated by TLRs are emerging, with TLR-4 signalling requiring an additional adapter termed MyD88-adapter-like (Mal), which may regulate the expression of genes specific for the response required to eliminate infection by Gram-negative bacteria [3].
  • MAL is expressed in a subset of Hodgkin lymphoma and identifies a population of patients with poor prognosis [4].
  • We report the NMR structural characterization of the active Tat Mal variant that belongs to a highly virulent D-subtype HIV type-1 (HIV-1) strain (Mal) found mainly in Africa. A full Tat Mal protein (87 residues) is synthesized [5].
  • We genotyped 33 SNPs, including rs8177374, which encodes a leucine substitution at Ser180 of Mal. We found that heterozygous carriage of this variant associated independently with all four infectious diseases in the different study populations [6].
  • Our results also indicate that LPS and protein I/II induced phosphorylation of Etk and Mal in rheumatoid arthritis FLS via a FAK-dependent pathway [7].

Psychiatry related information on TIRAP

  • Outcome measures included the Motor Activity Log for very low functioning patients (Grade 5 MAL), upper extremity portion of the Fugl-Meyer Motor Assessment, Graded Wolf Motor Function Test - for very low functioning patients (gWMFT- Grade 5), and Modified Ashworth Scale [8].

High impact information on TIRAP


Biological context of TIRAP

  • Results of this work indicate differences with a previously published bovine sequence for LY96 and a predicted sequence in the GenBank database for TIRAP based on the most recent assembly of the bovine genome [13].
  • Future studies on Mal will reveal specificities in signal transduction by different TLRs, which may ultimately provide molecular explanations for specificities in the innate immune response to infection [14].
  • TIRAP mediates endotoxin-induced NF-kappaB activation and apoptosis in endothelial cells [15].
  • In comparison to the 558CC genotype, the 558TT genotype was associated with decreased whole-blood interleukin-6 production, which suggests that TIRAP influences disease susceptibility by modulating the inflammatory response.Conclusions [16].
  • The TIRAP single-nucleotide polymorphism (SNP) C558T was associated with increased susceptibility to TB, with a 558T allele frequency of 0.035 in control samples versus 0.074 in case patients (odds ratio [OR], 2.25; P<.001) [16].

Anatomical context of TIRAP

  • Moreover, we used human alveolar macrophages to examine the role of TIRAP signaling in the human system [2].
  • Recently, a new signaling molecule, TIRAP, has been identified that mediates LPS-induced NF-kappaB signaling in monocytes and macrophages [15].
  • Conditioned media from synovial membrane cell cultures stimulated human macrophages in a MyD88- and Mal-dependent manner, suggesting the release of a TLR ligand(s) from these cells [17].
  • Heterologous overexpression in COS-7 cells of the fluorescently-tagged human MAL, a tetra-spanning, lipid-raft-associated protein, significantly slowed and limited membrane pore expansion and percolation [18].
  • MAL, a gene that encodes a protein associated with lipid rafts in T and epithelial cells, is overexpressed in a majority of MLBLs and has been reported in a minority of cHLs [4].

Associations of TIRAP with chemical compounds

  • These data identify TIRAP as a dual functioning signaling molecule and suggest the presence of a MyD88-independent LPS signaling pathway in human endothelial cells [15].
  • When overexpressed we have found that Mal undergoes tyrosine phosphorylation [19].
  • Three possible phospho-accepting tyrosines were identified at positions 86, 106, and 187, and two mutant forms of Mal in which tyrosines 86 and 187 were mutated to phenylalanine acted as dominant negative inhibitors of NF-kappaB activation by lipopolysaccharide (LPS) [19].
  • Neither theoretical nor experimental data suggest a direct role for the conserved proline in the BB-loop in the association of TLR4, Mal, and MyD88 [20].
  • Ascorbate was a much more effective electron donor than Mal, suggesting it has a physiological role in activation of cyclic electron flow around PSI [21].

Regulatory relationships of TIRAP


Other interactions of TIRAP

  • Mal interacts with tumor necrosis factor receptor-associated factor (TRAF)-6 to mediate NF-kappaB activation by toll-like receptor (TLR)-2 and TLR4 [26].
  • These results identify a specific role for Mal in TLR-mediated signaling in regulating NF-kappaB-dependent gene transcription via its interaction with TRAF6 [26].
  • As is the case in MyD88 and TIRAP, overexpression of TRIF activated the NF-kappaB-dependent promoter [22].
  • Furthermore, TRIF, but neither MyD88 nor TIRAP, activated the IFN-beta promoter [22].
  • In this study we show for the first time that activation of Rac1 leads to HIV-LTR trans-activation, and this is mediated through TIRAP [1].
  • Overexpression of Y86A- and Y106A-Mal in 293/TLR4/MD-2 cells exerted dominant-negative effects on TLR4-inducible p38 phosphorylation and NF-kappaB reporter activation to the extent comparable with P125H-Mal-mediated suppression [27].

Analytical, diagnostic and therapeutic context of TIRAP

  • This effect was abrogated by expression of dominant-negative versions of MyD88 or Mal, key signal transducers for TLRs, thereby implicating them as potential anti-inflammatory agents for CF [28].
  • True axial length (AL) of the silicone oil-filled (viscosity 1300 centistokes) eye can be estimated from the measured AL (MAL) obtained on A and/or B scan echography, by multiplying MAL by a conversion factor of 0.71 [29].


  1. Rac1 and Toll-IL-1 receptor domain-containing adapter protein mediate Toll-like receptor 4 induction of HIV-long terminal repeat. Equils, O., Madak, Z., Liu, C., Michelsen, K.S., Bulut, Y., Lu, D. J. Immunol. (2004) [Pubmed]
  2. Toll-IL-1 receptor domain-containing adaptor protein is critical for early lung immune responses against Escherichia coli lipopolysaccharide and viable Escherichia coli. Jeyaseelan, S., Manzer, R., Young, S.K., Yamamoto, M., Akira, S., Mason, R.J., Worthen, G.S. J. Immunol. (2005) [Pubmed]
  3. Signal transduction pathways activated by the IL-1 receptor/toll-like receptor superfamily. O'Neill, L.A. Curr. Top. Microbiol. Immunol. (2002) [Pubmed]
  4. MAL is expressed in a subset of Hodgkin lymphoma and identifies a population of patients with poor prognosis. Hsi, E.D., Sup, S.J., Alemany, C., Tso, E., Skacel, M., Elson, P., Alonso, M.A., Pohlman, B. Am. J. Clin. Pathol. (2006) [Pubmed]
  5. Homonuclear (1)H-NMR assignment and structural characterization of human immunodeficiency virus type 1 Tat Mal protein. Grégoire, C., Péloponèse, J.M., Esquieu, D., Opi, S., Campbell, G., Solomiac, M., Lebrun, E., Lebreton, J., Loret, E.P. Biopolymers (2001) [Pubmed]
  6. A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis. Khor, C.C., Chapman, S.J., Vannberg, F.O., Dunne, A., Murphy, C., Ling, E.Y., Frodsham, A.J., Walley, A.J., Kyrieleis, O., Khan, A., Aucan, C., Segal, S., Moore, C.E., Knox, K., Campbell, S.J., Lienhardt, C., Scott, A., Aaby, P., Sow, O.Y., Grignani, R.T., Sillah, J., Sirugo, G., Peshu, N., Williams, T.N., Maitland, K., Davies, R.J., Kwiatkowski, D.P., Day, N.P., Yala, D., Crook, D.W., Marsh, K., Berkley, J.A., O'Neill, L.A., Hill, A.V. Nat. Genet. (2007) [Pubmed]
  7. Etk/BMX, a Btk family tyrosine kinase, and Mal contribute to the cross-talk between MyD88 and FAK pathways. Semaan, N., Alsaleh, G., Gottenberg, J.E., Wachsmann, D., Sibilia, J. J. Immunol. (2008) [Pubmed]
  8. A treatment for a chronic stroke patient with a plegic hand combining CI therapy with conventional rehabilitation procedures: Case report. Taub, E., Uswatt, G., Bowman, M.H., Taub, E., Uswatte, G., Delgado, A., Bryson, C., Morris, D.M., McKay, S., Mark, V.W. NeuroRehabilitation. (2006) [Pubmed]
  9. Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling. Kagan, J.C., Medzhitov, R. Cell (2006) [Pubmed]
  10. Recognition and signaling by toll-like receptors. West, A.P., Koblansky, A.A., Ghosh, S. Annu. Rev. Cell Dev. Biol. (2006) [Pubmed]
  11. Intestinal myofibroblasts in innate immune responses of the intestine. Otte, J.M., Rosenberg, I.M., Podolsky, D.K. Gastroenterology (2003) [Pubmed]
  12. TRIF-GEFH1-RhoB pathway is involved in MHCII expression on dendritic cells that is critical for CD4 T-cell activation. Kamon, H., Kawabe, T., Kitamura, H., Lee, J., Kamimura, D., Kaisho, T., Akira, S., Iwamatsu, A., Koga, H., Murakami, M., Hirano, T. EMBO J. (2006) [Pubmed]
  13. Cloning and radiation hybrid mapping of bovine toll-like receptor-4 (TLR-4) signaling molecules. Connor, E.E., Cates, E.A., Williams, J.L., Bannerman, D.D. Vet. Immunol. Immunopathol. (2006) [Pubmed]
  14. Mal and MyD88: adapter proteins involved in signal transduction by Toll-like receptors. O'Neill, L.A., Dunne, A., Edjeback, M., Gray, P., Jefferies, C., Wietek, C. J. Endotoxin Res. (2003) [Pubmed]
  15. TIRAP mediates endotoxin-induced NF-kappaB activation and apoptosis in endothelial cells. Bannerman, D.D., Erwert, R.D., Winn, R.K., Harlan, J.M. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  16. A polymorphism in toll-interleukin 1 receptor domain containing adaptor protein is associated with susceptibility to meningeal tuberculosis. Hawn, T.R., Dunstan, S.J., Thwaites, G.E., Simmons, C.P., Thuong, N.T., Lan, N.T., Quy, H.T., Chau, T.T., Hieu, N.T., Rodrigues, S., Janer, M., Zhao, L.P., Hien, T.T., Farrar, J.J., Aderem, A. J. Infect. Dis. (2006) [Pubmed]
  17. The Toll-Like Receptor Adaptor Proteins MyD88 and Mal/TIRAP Contribute to the Inflammatory and Destructive Processes in a Human Model of Rheumatoid Arthritis. Sacre, S.M., Andreakos, E., Kiriakidis, S., Amjadi, P., Lundberg, A., Giddins, G., Feldmann, M., Brennan, F., Foxwell, B.M. Am. J. Pathol. (2007) [Pubmed]
  18. The MAL proteolipid restricts detergent-mediated membrane pore expansion and percolation. Dukhovny, A., Goldstein Magal, L., Hirschberg, K. Mol. Membr. Biol. (2006) [Pubmed]
  19. MyD88 adapter-like (Mal) is phosphorylated by Bruton's tyrosine kinase during TLR2 and TLR4 signal transduction. Gray, P., Dunne, A., Brikos, C., Jefferies, C.A., Doyle, S.L., O'Neill, L.A. J. Biol. Chem. (2006) [Pubmed]
  20. Structural complementarity of Toll/interleukin-1 receptor domains in Toll-like receptors and the adaptors Mal and MyD88. Dunne, A., Ejdeback, M., Ludidi, P.L., O'Neill, L.A., Gay, N.J. J. Biol. Chem. (2003) [Pubmed]
  21. Characterization of photosynthetic electron transport in bundle sheath cells of maize. I. Ascorbate effectively stimulates cyclic electron flow around PSI. Ivanov, B., Asada, K., Kramer, D.M., Edwards, G. Planta (2005) [Pubmed]
  22. Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling. Yamamoto, M., Sato, S., Mori, K., Hoshino, K., Takeuchi, O., Takeda, K., Akira, S. J. Immunol. (2002) [Pubmed]
  23. Protein kinase Cdelta binds TIRAP/Mal to participate in TLR signaling. Kubo-Murai, M., Hazeki, K., Sukenobu, N., Yoshikawa, K., Nigorikawa, K., Inoue, K., Yamamoto, T., Matsumoto, M., Seya, T., Inoue, N., Hazeki, O. Mol. Immunol. (2007) [Pubmed]
  24. Poxvirus protein N1L targets the I-kappaB kinase complex, inhibits signaling to NF-kappaB by the tumor necrosis factor superfamily of receptors, and inhibits NF-kappaB and IRF3 signaling by toll-like receptors. DiPerna, G., Stack, J., Bowie, A.G., Boyd, A., Kotwal, G., Zhang, Z., Arvikar, S., Latz, E., Fitzgerald, K.A., Marshall, W.L. J. Biol. Chem. (2004) [Pubmed]
  25. NF-kappaB activation by the Toll-IL-1 receptor domain protein MyD88 adapter-like is regulated by caspase-1. Miggin, S.M., Pålsson-McDermott, E., Dunne, A., Jefferies, C., Pinteaux, E., Banahan, K., Murphy, C., Moynagh, P., Yamamoto, M., Akira, S., Rothwell, N., Golenbock, D., Fitzgerald, K.A., O'Neill, L.A. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  26. Mal interacts with tumor necrosis factor receptor-associated factor (TRAF)-6 to mediate NF-kappaB activation by toll-like receptor (TLR)-2 and TLR4. Mansell, A., Brint, E., Gould, J.A., O'Neill, L.A., Hertzog, P.J. J. Biol. Chem. (2004) [Pubmed]
  27. Tyrosine phosphorylation of MyD88 adapter-like (Mal) is critical for signal transduction and blocked in endotoxin tolerance. Piao, W., Song, C., Chen, H., Wahl, L.M., Fitzgerald, K.A., O'Neill, L.A., Medvedev, A.E. J. Biol. Chem. (2008) [Pubmed]
  28. TLR-induced inflammation in cystic fibrosis and non-cystic fibrosis airway epithelial cells. Greene, C.M., Carroll, T.P., Smith, S.G., Taggart, C.C., Devaney, J., Griffin, S., O'neill, S.J., McElvaney, N.G. J. Immunol. (2005) [Pubmed]
  29. Biometry of the silicone oil-filled eye: II. Murray, D.C., Durrani, O.M., Good, P., Benson, M.T., Kirkby, G.R. Eye (London, England) (2002) [Pubmed]
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