Gene Symbol: Tirap
Description: toll-interleukin 1 receptor (TIR) domain-containing adaptor protein
Alias: AA407980, C130027E04Rik, Mal, Tlr4ap, Wyatt, toll/interleukin-1 receptor domain-containing adapter protein, TIR domain-containing adapter protein, Toll-like receptor 4 adaptor protein, adaptor protein Wyatt, myD88 adapter-like protein
Species: mouse
Products:     Tirap

Top Publications

  1. Fitzgerald K, Palsson McDermott E, Bowie A, Jefferies C, Mansell A, Brady G, et al. Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature. 2001;413:78-83 pubmed
    ..Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TIR-domain-containing protein in the human genome...
  2. Yamamoto M, Sato S, Hemmi H, Sanjo H, Uematsu S, Kaisho T, et al. Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature. 2002;420:324-9 pubmed
    ..Another adaptor, TIRAP (also known as Mal), has been cloned as a molecule that specifically associates with TLR4 and thus may be ..
  3. Horng T, Barton G, Flavell R, Medzhitov R. The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature. 2002;420:329-33 pubmed
    ..b>TIRAP, an adaptor protein in the TLR signalling pathway, has been identified and shown to function downstream of TLR4 (..
  4. Horng T, Barton G, Medzhitov R. TIRAP: an adapter molecule in the Toll signaling pathway. Nat Immunol. 2001;2:835-41 pubmed
    ..We have identified and characterized a Toll-interleukin 1 receptor (TIR) domain-containing adapter protein (TIRAP) and have shown that it controls activation of MyD88-independent signaling pathways downstream of TLR4...
  5. Fremond C, Togbe D, Doz E, Rose S, Vasseur V, Maillet I, et al. IL-1 receptor-mediated signal is an essential component of MyD88-dependent innate response to Mycobacterium tuberculosis infection. J Immunol. 2007;179:1178-89 pubmed
    ..Mice deficient for IL-1R1, IL-18R, or Toll-IL-1R domain-containing adaptor protein (TIRAP) were compared with MyD88-deficient mice in an acute model of aerogenic MTB infection...
  6. Fitzgerald K, Rowe D, Barnes B, Caffrey D, Visintin A, Latz E, et al. LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF. J Exp Med. 2003;198:1043-55 pubmed
    ..TRAM interacts with TRIF, MyD88 adaptor-like protein (Mal)/TIRAP, and TLR4 but not with TLR3...
  7. Kagan J, Su T, Horng T, Chow A, Akira S, Medzhitov R. TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta. Nat Immunol. 2008;9:361-8 pubmed publisher
    Toll-like receptor 4 (TLR4) induces two distinct signaling pathways controlled by the TIRAP-MyD88 and TRAM-TRIF pairs of adaptor proteins, which elicit the production of proinflammatory cytokines and type I interferons, respectively...
  8. Miggin S, Palsson McDermott E, Dunne A, Jefferies C, Pinteaux E, Banahan K, et al. NF-kappaB activation by the Toll-IL-1 receptor domain protein MyD88 adapter-like is regulated by caspase-1. Proc Natl Acad Sci U S A. 2007;104:3372-7 pubmed
    ..Both use the adapter proteins MyD88 and MyD88 adapter-like (Mal) to activate signaling pathways...
  9. Bechtel C, Gebhart J, Tatro J, Kiss Toth E, Wilkinson J, Greenfield E. Particle-Induced Osteolysis Is Mediated by TIRAP/Mal in Vitro and in Vivo: Dependence on Adherent Pathogen-Associated Molecular Patterns. J Bone Joint Surg Am. 2016;98:285-94 pubmed publisher
    ..for TLR-2 and TLR-4 known as toll/interleukin-1 receptor domain-containing adapter protein/MyD88 adapter-like (TIRAP/Mal)...

More Information


  1. Verstak B, Nagpal K, Bottomley S, Golenbock D, Hertzog P, Mansell A. MyD88 adapter-like (Mal)/TIRAP interaction with TRAF6 is critical for TLR2- and TLR4-mediated NF-kappaB proinflammatory responses. J Biol Chem. 2009;284:24192-203 pubmed publisher
    ..MyD88 adapter-like (Mal), also termed TIRAP, is involved in bridging MyD88 to the receptor complex for TLR-2 and TLR4 signaling in response to bacterial ..
  2. Corr S, Palsson McDermott E, Grishina I, Barry S, Aviello G, Bernard N, et al. MyD88 adaptor-like (Mal) functions in the epithelial barrier and contributes to intestinal integrity via protein kinase C. Mucosal Immunol. 2014;7:57-67 pubmed publisher
    MyD88 adapter-like (Mal)-deficient mice displayed increased susceptibility to oral but not intraperitoneal infection with Salmonella Typhimurium...
  3. Troutman T, Hu W, Fulenchek S, Yamazaki T, Kurosaki T, Bazan J, et al. Role for B-cell adapter for PI3K (BCAP) as a signaling adapter linking Toll-like receptors (TLRs) to serine/threonine kinases PI3K/Akt. Proc Natl Acad Sci U S A. 2012;109:273-8 pubmed publisher
    ..Our results demonstrate that BCAP is a unique TIR domain-containing TLR signaling adapter crucial for linking TLRs to PI3K activation and regulating the inflammatory response. ..
  4. Togbe D, Schnyder Candrian S, Schnyder B, Doz E, Noulin N, Janot L, et al. Toll-like receptor and tumour necrosis factor dependent endotoxin-induced acute lung injury. Int J Exp Pathol. 2007;88:387-91 pubmed
    ..myeloid differentiation factor 88 (MyD88) and Toll/Interleukin-1 receptor (TIR)-domain-containing adaptor protein (TIRAP), but independent of TIR-domain-containing adaptor-inducing interferon-beta (TRIF)...
  5. Lundberg A, Ketelhuth D, Johansson M, Gerdes N, Liu S, Yamamoto M, et al. Toll-like receptor 3 and 4 signalling through the TRIF and TRAM adaptors in haematopoietic cells promotes atherosclerosis. Cardiovasc Res. 2013;99:364-73 pubmed publisher
    ..of TLRs in immune cells are pro-atherogenic, we analysed the role of the TLR-specific adaptors MyD88 adaptor-like (MAL), TRIF-related adaptor molecule (TRAM), and TIR-domain-containing adaptor-inducing interferon-? (TRIF) in ..
  6. Cole L, Laird M, Seekatz A, Santiago A, Jiang Z, Barry E, et al. Phagosomal retention of Francisella tularensis results in TIRAP/Mal-independent TLR2 signaling. J Leukoc Biol. 2010;87:275-81 pubmed publisher
    ..The two adaptor proteins associated with TLR2-mediated signaling are MyD88 and TIRAP. Although MyD88 is absolutely required for the Ft-induced macrophage cytokine response, the requirement for TIRAP ..
  7. Tesar B, Jiang D, Liang J, Palmer S, Noble P, Goldstein D. The role of hyaluronan degradation products as innate alloimmune agonists. Am J Transplant. 2006;6:2622-35 pubmed
    ..In conclusion, our study suggests that fragments of hyaluronan can act as innate immune agonists that activate alloimmunity. ..
  8. Gravina H, Goes A, Murta S, Ropert C. MyD88 Adapter-like (Mal)/TIRAP Is Required for Cytokine Production by Splenic Ly6CloTLR2hi but Not by Ly6ChiTLR2hi Monocytes during Trypanosoma cruzi Infection. J Biol Chem. 2016;291:23832-23841 pubmed
    ..e. TLR2 or TLR9 agonists). Another difference between the monocyte populations is that the adapter Mal (encoded by TIRAP) has appeared crucial for the cytokine production by Ly6Clo but not by Ly6Chi monocytes...
  9. Scott M, Liu S, Shapiro R, Vodovotz Y, Billiar T. Endotoxin uptake in mouse liver is blocked by endotoxin pretreatment through a suppressor of cytokine signaling-1-dependent mechanism. Hepatology. 2009;49:1695-708 pubmed publisher
    ..SOCS1 is known to interact with Toll/IL-1 receptor associated protein (TIRAP) and cause TIRAP ubiquitination and degradation, which regulates TLR signaling...
  10. Brown G, McIntyre T. Lipopolysaccharide signaling without a nucleus: kinase cascades stimulate platelet shedding of proinflammatory IL-1?-rich microparticles. J Immunol. 2011;186:5489-96 pubmed publisher
    ..cell-penetrating chimeric peptide inhibitors, and gene-targeted animals to show splicing required MyD88 and TIRAP, and IRAK1/4, Akt, and JNK phosphorylation and activation...
  11. Hise A, Daehnel K, Gillette Ferguson I, Cho E, McGarry H, Taylor M, et al. Innate immune responses to endosymbiotic Wolbachia bacteria in Brugia malayi and Onchocerca volvulus are dependent on TLR2, TLR6, MyD88, and Mal, but not TLR4, TRIF, or TRAM. J Immunol. 2007;178:1068-76 pubmed
    ..whereas responses were absent in macrophages from MyD88(-/-) and Toll/IL-1R domain-containing adaptor protein (TIRAP)/MyD88 adaptor-like (Mal) deficient mice...
  12. Kobayashi T, Takahashi K, Nagai Y, Shibata T, Otani M, Izui S, et al. Tonic B cell activation by Radioprotective105/MD-1 promotes disease progression in MRL/lpr mice. Int Immunol. 2008;20:881-91 pubmed publisher
    ..Our results suggest that RP105-dependent tonic B cell activation has a pathogenic role in MRL/lpr mice. ..
  13. Hoebe K, Georgel P, Rutschmann S, Du X, Mudd S, Crozat K, et al. CD36 is a sensor of diacylglycerides. Nature. 2005;433:523-7 pubmed
    ..Already known as a receptor for endogenous molecules, CD36 is also a selective and nonredundant sensor of microbial diacylglycerides that signal via the TLR2/6 heterodimer. ..
  14. Nguyen T, Kim Y, Kim T, Le O, Kim J, Kang H, et al. Phosphatidylinositol 4-phosphate 5-kinase ? facilitates Toll-like receptor 4-mediated microglial inflammation through regulation of the Toll/interleukin-1 receptor domain-containing adaptor protein (TIRAP) location. J Biol Chem. 2013;288:5645-59 pubmed publisher
    ..is also known to mediate plasma membrane localization of the Toll/IL-1 receptor domain-containing adaptor protein (TIRAP), required for the MyD88-dependent Toll-like receptor (TLR) 4 signaling pathway...
  15. Miao E, Leaf I, Treuting P, Mao D, Dors M, Sarkar A, et al. Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nat Immunol. 2010;11:1136-42 pubmed publisher
    ..This demonstrates that activation of caspase-1 clears intracellular bacteria in vivo independently of IL-1? and IL-18 and establishes pyroptosis as an efficient mechanism of bacterial clearance by the innate immune system...
  16. Ma J, Bang B, Lu J, Eun S, Otsuka M, Croft M, et al. The TNF family member 4-1BBL sustains inflammation by interacting with TLR signaling components during late-phase activation. Sci Signal. 2013;6:ra87 pubmed publisher
    ..We showed that Toll-interleukin-1 receptor (TIR) domain-containing adaptor protein (TIRAP) and the kinase IRAK2 interacted with 4-1BBL to mediate late-phase TLR4 signaling...
  17. Aviello G, Corr S, Johnston D, O Neill L, Fallon P. MyD88 adaptor-like (Mal) regulates intestinal homeostasis and colitis-associated colorectal cancer in mice. Am J Physiol Gastrointest Liver Physiol. 2014;306:G769-78 pubmed publisher
    ..The protein MyD88 adaptor-like (Mal/TIRAP) serves as a bridge between TLR2/TLR4- and MyD88-mediated signaling to orchestrate downstream inflammatory ..
  18. Santos Sierra S, Deshmukh S, Kalnitski J, Küenzi P, Wymann M, Golenbock D, et al. Mal connects TLR2 to PI3Kinase activation and phagocyte polarization. EMBO J. 2009;28:2018-27 pubmed publisher
    ..to essentially require both adaptor proteins MyD88 (myeloid differentiation primary response gene 88) and Mal/TIRAP (MyD88-adapter-like/TIR-domain-containing adaptor protein)...
  19. Schilling D, Thomas K, Nixdorff K, Vogel S, Fenton M. Toll-like receptor 4 and Toll-IL-1 receptor domain-containing adapter protein (TIRAP)/myeloid differentiation protein 88 adapter-like (Mal) contribute to maximal IL-6 expression in macrophages. J Immunol. 2002;169:5874-80 pubmed
    ..expression via a mechanism that requires the adapter protein Toll-IL-1R domain-containing adapter protein (TIRAP)/myeloid differentiation protein 88 (MyD88) adapter-like (Mal), but not the adapter protein MyD88...
  20. Zhang Y, Xu C, Cardell L. Long-term exposure to IL-1beta enhances Toll-IL-1 receptor-mediated inflammatory signaling in murine airway hyperresponsiveness. Eur Cytokine Netw. 2009;20:148-56 pubmed publisher
    ..Understanding cytokine-induced activation of the Toll-IL-1 receptor-mediated inflammatory signaling mechanisms may provide new options for the treatment of airway inflammation and AHR. ..
  21. Smoak K, Aloor J, Madenspacher J, Merrick B, Collins J, Zhu X, et al. Myeloid differentiation primary response protein 88 couples reverse cholesterol transport to inflammation. Cell Metab. 2010;11:493-502 pubmed publisher
  22. Leal S, Cowden S, Hsia Y, Ghannoum M, Momany M, Pearlman E. Distinct roles for Dectin-1 and TLR4 in the pathogenesis of Aspergillus fumigatus keratitis. PLoS Pathog. 2010;6:e1000976 pubmed publisher
    ..We also found that TRIF(-/-) and TIRAP(-/-) mice exhibited no fungal-killing defects, but that MyD88(-/-) and IL-1R1(-/-) mice were unable to regulate ..
  23. Khor C, Chapman S, Vannberg F, Dunne A, Murphy C, Ling E, et al. A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis. Nat Genet. 2007;39:523-8 pubmed
    ..The adaptor protein Mal (also known as TIRAP), encoded by TIRAP (MIM 606252), mediates downstream signaling of TLR2 and TLR4 (refs. 4-6)...
  24. Mansell A, Smith R, Doyle S, Gray P, Fenner J, Crack P, et al. Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation. Nat Immunol. 2006;7:148-55 pubmed
    ..The adaptor protein Mal is specifically involved in signaling via TLR2 and TLR4...
  25. Kennedy C, Najdovska M, Tye H, McLeod L, Yu L, Jarnicki A, et al. Differential role of MyD88 and Mal/TIRAP in TLR2-mediated gastric tumourigenesis. Oncogene. 2014;33:2540-6 pubmed publisher
    ..However, little is known about the in vivo role of MyD88 adapter-like (Mal)/TIR-domain containing adapter protein (TIRAP), which is restricted to facilitating TLR4 and TLR2 signalling...
  26. Montminy S, Khan N, McGrath S, Walkowicz M, Sharp F, Conlon J, et al. Virulence factors of Yersinia pestis are overcome by a strong lipopolysaccharide response. Nat Immunol. 2006;7:1066-73 pubmed
    ..required TLR4, the adaptor protein MyD88 and coreceptor MD-2 and was considerably enhanced by CD14 and the adaptor Mal. Both innate and adaptive responses were required for sterilizing immunity against the modified strain, and ..
  27. Kagan J, Medzhitov R. Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling. Cell. 2006;125:943-55 pubmed
    ..Signaling downstream from TLRs is initiated by the recruitment of adaptor proteins, including MyD88 and TIRAP. These adaptors play essential roles in TLR signaling, but the mechanism of their function is currently unknown...
  28. Choi Y, Jung J, Chung H, Im E, Rhee S. PTEN regulates TLR5-induced intestinal inflammation by controlling Mal/TIRAP recruitment. FASEB J. 2013;27:243-54 pubmed publisher
    ..responses, we hypothesized that PTEN regulated TLR5-induced responses by controlling the involvement of Mal in TLR5 engagement...
  29. Talbot S, Tötemeyer S, Yamamoto M, Akira S, Hughes K, Gray D, et al. Toll-like receptor 4 signalling through MyD88 is essential to control Salmonella enterica serovar typhimurium infection, but not for the initiation of bacterial clearance. Immunology. 2009;128:472-83 pubmed publisher
    ..TLR4 signals through the adapter proteins Mal/MyD88 and TRIF-related adaptor molecule (TRAM)/TIR-domain-containing adaptor-inducing interferon-b (TRIF)...
  30. Hajishengallis G, Wang M, Liang S. Induction of distinct TLR2-mediated proinflammatory and proadhesive signaling pathways in response to Porphyromonas gingivalis fimbriae. J Immunol. 2009;182:6690-6 pubmed publisher
    ..pathway is dependent on the adaptor molecules Toll/IL-1 receptor domain-containing adaptor protein (also known as Mal) and MyD88, the proadhesive pathway is Toll/IL-1 receptor domain-containing adaptor protein/MyD88-independent and ..
  31. Siednienko J, Halle A, Nagpal K, Golenbock D, Miggin S. TLR3-mediated IFN-? gene induction is negatively regulated by the TLR adaptor MyD88 adaptor-like. Eur J Immunol. 2010;40:3150-60 pubmed publisher
    ..Herein, we sought to perform analysis to definitively assign a mechanistic role for MyD88 adaptor-like (Mal), an activator of TLR2/4 signalling, in the negative regulation of TLR3/TRIF signalling...
  32. Lysakova Devine T, Keogh B, Harrington B, Nagpal K, Halle A, Golenbock D, et al. Viral inhibitory peptide of TLR4, a peptide derived from vaccinia protein A46, specifically inhibits TLR4 by directly targeting MyD88 adaptor-like and TRIF-related adaptor molecule. J Immunol. 2010;185:4261-71 pubmed publisher
    ..Indeed, VIPER directly interacted with the TLR4 adaptor proteins MyD88 adaptor-like (Mal) and TRIF-related adaptor molecule (TRAM)...
  33. Togbe D, Schofield L, Grau G, Schnyder B, Boissay V, Charron S, et al. Murine cerebral malaria development is independent of toll-like receptor signaling. Am J Pathol. 2007;170:1640-8 pubmed
    ..we infected mice deficient for single TLR1, -2, -3, -4, -6, -7, or -9 and their adapter proteins MyD88, TIRAP, and TRIF...
  34. Kenny E, Talbot S, Gong M, Golenbock D, Bryant C, O Neill L. MyD88 adaptor-like is not essential for TLR2 signaling and inhibits signaling by TLR3. J Immunol. 2009;183:3642-51 pubmed publisher
    Although a clear role for the adaptor protein myeloid differentiation factor-88 (MyD88) adaptor-like (Mal, or TIRAP) in TLR4 signaling has been demonstrated, there is limited information on its role in TLR2 signaling...
  35. Sun Y, Karmakar M, Roy S, Ramadan R, Williams S, Howell S, et al. TLR4 and TLR5 on corneal macrophages regulate Pseudomonas aeruginosa keratitis by signaling through MyD88-dependent and -independent pathways. J Immunol. 2010;185:4272-83 pubmed publisher
    ..IL-1? and IL-1? are also produced, which activate an IL-1R1/MyD88-positive feedback loop in macrophages and IL-1R on other resident cells in the cornea. ..
  36. Bonilla D, Bhattacharya A, Sha Y, Xu Y, Xiang Q, Kan A, et al. Autophagy regulates phagocytosis by modulating the expression of scavenger receptors. Immunity. 2013;39:537-47 pubmed publisher
    ..These insights increase our understanding of the host-pathogen relationship and suggest that therapeutic strategies should be designed to include modulation of both phagocytosis and autophagy. ..
  37. Gandhi A, Guo T, Shah P, Moorthy B, Ghose R. Chlorpromazine-induced hepatotoxicity during inflammation is mediated by TIRAP-dependent signaling pathway in mice. Toxicol Appl Pharmacol. 2013;266:430-8 pubmed publisher
    ..of TLRs recruits the first adaptor protein, Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) to the TIR domain of TLRs leading to the activation of the downstream kinase, c-Jun-N-terminal kinase (JNK)...
  38. Wang S, Shi W, Wang X, Velky L, Greenlee S, Wang M, et al. Mapping, genetic isolation, and characterization of genetic loci that determine resistance to atherosclerosis in C3H mice. Arterioscler Thromb Vasc Biol. 2007;27:2671-6 pubmed
    ..We have also determined that Tlr4 on the C3H ApoE(-/-) background does not contribute to early lesion development. *Ath29 is referred to as Ath22 in Su et al 2006. ..
  39. Layoun A, Huang H, Calvé A, Santos M. Toll-like receptor signal adaptor protein MyD88 is required for sustained endotoxin-induced acute hypoferremic response in mice. Am J Pathol. 2012;180:2340-50 pubmed publisher
    ..Together, these results suggest that targeting specific TLR signaling pathways by affecting the function of adaptor molecules may provide new strategies to counteract iron sequestration within macrophages during inflammation. ..
  40. Li Z, Potts Kant E, Garantziotis S, Foster W, Hollingsworth J. Hyaluronan signaling during ozone-induced lung injury requires TLR4, MyD88, and TIRAP. PLoS ONE. 2011;6:e27137 pubmed publisher
    ..Using a murine model of AHR, C57BL/6J, TLR4-/-, MyD88-/-, and TIRAP-/- mice were characterized for AHR after exposure to either ozone (1 ppm × 3 h) or HA fragments...
  41. Gong L, Wang H, Sun X, Liu C, Duan C, Cai R, et al. Toll-Interleukin 1 Receptor domain-containing adaptor protein positively regulates BV2 cell M1 polarization. Eur J Neurosci. 2016;43:1674-82 pubmed publisher
    ..Toll-like receptor (TLR)4 is important for microglial polarization. TIR domain-containing adaptor protein (TIRAP) is an intracellular adaptor protein, which is responsible for the early phase of TLR4 activation...
  42. Nel H, Hams E, Saunders S, Mangan N, Smith P, Atzberger A, et al. Impaired basophil induction leads to an age-dependent innate defect in type 2 immunity during helminth infection in mice. J Immunol. 2011;186:4631-9 pubmed publisher
    ..brasiliensis. The defect in juvenile mice with regard to helminth-induced innate basophil-mediated type 2 response is relevant to allergic conditions. ..
  43. Jiang Z, Georgel P, Li C, Choe J, Crozat K, Rutschmann S, et al. Details of Toll-like receptor:adapter interaction revealed by germ-line mutagenesis. Proc Natl Acad Sci U S A. 2006;103:10961-6 pubmed
    ..Moreover, MyD88 engages individual TLRs differently, suggesting the feasibility of selective pharmacologic TIR domain receptor blockade. ..
  44. Cook P, Tötemeyer S, Stevenson C, Fitzgerald K, Yamamoto M, Akira S, et al. Salmonella-induced SipB-independent cell death requires Toll-like receptor-4 signalling via the adapter proteins Tram and Trif. Immunology. 2007;122:222-9 pubmed
    ..membrane of Gram-negative bacteria and is recognized by Toll-like receptor 4, signalling via the adapter proteins Mal, MyD88, Tram and Trif. Here we show that S...
  45. Ferrero M, Hielpos M, Carvalho N, Barrionuevo P, Corsetti P, Giambartolomei G, et al. Key role of Toll-like receptor 2 in the inflammatory response and major histocompatibility complex class ii downregulation in Brucella abortus-infected alveolar macrophages. Infect Immun. 2014;82:626-39 pubmed publisher
    ..Both the modest nature of the latter and the modulation of MHC-II expression by the bacterium may contribute to such survival. ..
  46. Piao W, Shirey K, Ru L, Lai W, Szmacinski H, Snyder G, et al. A Decoy Peptide that Disrupts TIRAP Recruitment to TLRs Is Protective in a Murine Model of Influenza. Cell Rep. 2015;11:1941-52 pubmed publisher
    ..Cell imaging, co-immunoprecipitation, and in vitro studies demonstrated that 2R9 preferentially targets TIRAP. 2R9 diminished systemic cytokine responses elicited in vivo by synthetic TLR2 and TLR7 agonists; it inhibited the ..
  47. Chen C, Shi Y, Hearn A, Fitzgerald K, Golenbock D, Reed G, et al. MyD88-dependent IL-1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystals. J Clin Invest. 2006;116:2262-71 pubmed
    ..In contrast, other TIR adaptor molecules, TIRAP/Mal, TRIF, and TRAM, are not required for this process...
  48. Ulrichts P, Lemmens I, Lavens D, Beyaert R, Tavernier J. MAPPIT (mammalian protein-protein interaction trap) analysis of early steps in toll-like receptor signalling. Methods Mol Biol. 2009;517:133-44 pubmed publisher
    ..In the subsequent protocol, we describe the use of MAPPIT to study early events in Toll-like receptor (TLR) signalling. We here demonstrate a "signalling interaction cascade" from TLR4 to IRAK-1. ..
  49. Georgel P, Jiang Z, Kunz S, Janssen E, Mols J, Hoebe K, et al. Vesicular stomatitis virus glycoprotein G activates a specific antiviral Toll-like receptor 4-dependent pathway. Virology. 2007;362:304-13 pubmed publisher
    ..response pathway in which the adapter TRAM has predominant importance, absent any need for MyD88 or Mal, and with only a partial requirement for TRIF. Downstream of TRAM, IRF7 activation leads to a type I IFN response...
  50. Ahmad R, El Bassam S, Cordeiro P, Menezes J. Requirement of TLR2-mediated signaling for the induction of IL-15 gene expression in human monocytic cells by HSV-1. Blood. 2008;112:2360-8 pubmed publisher
    ..Interestingly, TIRAP/Mal, an adaptor molecule specifically recruited to TLR2 and TLR4, was also required for maximal up-regulation of ..
  51. Sakata Y, Dong J, Vallejo J, Huang C, Baker J, Tracey K, et al. Toll-like receptor 2 modulates left ventricular function following ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 2007;292:H503-9 pubmed
    ..Thus disruption of TLR2-mediated signaling may be helpful to induce immediate or delayed myocardial protection from ischemia-reperfusion injury. ..
  52. Suzuki N, Suzuki S, Duncan G, Millar D, Wada T, Mirtsos C, et al. Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature. 2002;416:750-6 pubmed
    ..In addition, animals lacking IRAK-4 are severely impaired in their responses to viral and bacterial challenges. Our results indicate that IRAK-4 has an essential role in innate immunity. ..
  53. Ní Cheallaigh C, Sheedy F, Harris J, Muñoz Wolf N, Lee J, West K, et al. A Common Variant in the Adaptor Mal Regulates Interferon Gamma Signaling. Immunity. 2016;44:368-79 pubmed publisher
    ..that are heterozygous for the common S180L polymorphism in the Toll-like receptor (TLR) adaptor Mal (encoded by TIRAP) are protected from a number of infectious diseases, including tuberculosis (TB), whereas those homozygous for the ..
  54. Jeyaseelan S, Young S, Yamamoto M, Arndt P, Akira S, Kolls J, et al. Toll/IL-1R domain-containing adaptor protein (TIRAP) is a critical mediator of antibacterial defense in the lung against Klebsiella pneumoniae but not Pseudomonas aeruginosa. J Immunol. 2006;177:538-47 pubmed
    ..TLRs are essential for innate immune defense. TIRAP (Toll/IL-1R domain-containing adaptor protein) is an adaptor in TLR1, TLR2, TLR4, and TLR6 signaling, whereas ..
  55. Dong J, Vallejo J, Tzeng H, Thomas J, Mann D. Innate immunity mediates myocardial preconditioning through Toll-like receptor 2 and TIRAP-dependent signaling pathways. Am J Physiol Heart Circ Physiol. 2010;298:H1079-87 pubmed publisher
    ..wild-type (WT) mice and mice deficient in TLR2 (TLR2D), TLR4 (TLR4D), and TIR domain-containing adapter protein (TIRAP-D) to ischemic preconditioning (IPC)...
  56. Eto A, Muta T, Yamazaki S, Takeshige K. Essential roles for NF-kappa B and a Toll/IL-1 receptor domain-specific signal(s) in the induction of I kappa B-zeta. Biochem Biophys Res Commun. 2003;301:495-501 pubmed
    ..These results indicate the existence of another signal essential for I kappa B-zeta induction, which is specifically mediated by the TIR domain-mediated signaling pathway. ..
  57. Biondo C, Signorino G, Costa A, Midiri A, Gerace E, Galbo R, et al. Recognition of yeast nucleic acids triggers a host-protective type I interferon response. Eur J Immunol. 2011;41:1969-79 pubmed publisher
    ..These data suggest that recognition of yeast nucleic acids by TLR7 and TLR9 triggers a host-protective IFN-?/? response. ..
  58. Greenhill C, Rose John S, Lissilaa R, Ferlin W, Ernst M, Hertzog P, et al. IL-6 trans-signaling modulates TLR4-dependent inflammatory responses via STAT3. J Immunol. 2011;186:1199-208 pubmed publisher
    ..Additional genetic approaches demonstrated that the TLR4/Mal pathway contributed to LPS hypersensitivity and increased IL-6 production in gp130(F/F) mice...
  59. Jeyaseelan S, Manzer R, Young S, Yamamoto M, Akira S, Mason R, et al. Toll-IL-1 receptor domain-containing adaptor protein is critical for early lung immune responses against Escherichia coli lipopolysaccharide and viable Escherichia coli. J Immunol. 2005;175:7484-95 pubmed
    ..Toll-IL-1R domain-containing adaptor protein (TIRAP) is a key molecule in the TLR4 and 2 signaling...
  60. Querec T, Bennouna S, Alkan S, Laouar Y, Gorden K, Flavell R, et al. Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity. J Exp Med. 2006;203:413-24 pubmed
  61. Baig M, Liu D, Muthu K, Roy A, Saqib U, Naim A, et al. Heterotrimeric complex of p38 MAPK, PKCδ, and TIRAP is required for AP1 mediated inflammatory response. Int Immunopharmacol. 2017;48:211-218 pubmed publisher
    ..of Protein kinase C delta type (PKCδ), Toll-Interleukin 1 Receptor (TIR) Domain Containing Adaptor Protein (TIRAP), and p38 proteins. TIRAP serves as an adaptor molecule which brings PKCδ and p38 in close proximity...
  62. Figgett W, Fairfax K, Vincent F, Le Page M, Katik I, Deliyanti D, et al. The TACI receptor regulates T-cell-independent marginal zone B cell responses through innate activation-induced cell death. Immunity. 2013;39:573-83 pubmed publisher
    ..These findings demonstrate an unappreciated role for TACI and its ligands in the regulation of AICD during T-cell-independent B cell responses. ..
  63. Dixit E, Boulant S, Zhang Y, Lee A, Odendall C, Shum B, et al. Peroxisomes are signaling platforms for antiviral innate immunity. Cell. 2010;141:668-81 pubmed publisher
    ..The interferon regulatory factor IRF1 plays a crucial role in regulating MAVS-dependent signaling from peroxisomes. These results establish that peroxisomes are an important site of antiviral signal transduction. ..
  64. Yamamoto M, Takeda K, Akira S. TIR domain-containing adaptors define the specificity of TLR signaling. Mol Immunol. 2004;40:861-8 pubmed
    ..Indeed, two additional TIR domain-containing adaptors, TIRAP/Mal and TRIF, have recently been identified. Both define the specific biological responses of each TLR.
  65. Alugupalli K, Akira S, Lien E, Leong J. MyD88- and Bruton's tyrosine kinase-mediated signals are essential for T cell-independent pathogen-specific IgM responses. J Immunol. 2007;178:3740-9 pubmed
    ..These results suggest that MyD88 specifically promotes T cell-independent BCR signaling and that, in the absence of Btk, this TLR-mediated stimulation is a required component of this signal. ..
  66. Wei B, Su T, Dalwadi H, Stephan R, Fujiwara D, Huang T, et al. Resident enteric microbiota and CD8+ T cells shape the abundance of marginal zone B cells. Eur J Immunol. 2008;38:3411-25 pubmed publisher
    ..Thus, members of certain enteric microbial communities link with CD8(+) T cells as a previously unappreciated mechanism that shapes innate immunity dependent on innate-like B cells. ..
  67. Ding A, Yu H, Yang J, Shi S, Ehrt S. Induction of macrophage-derived SLPI by Mycobacterium tuberculosis depends on TLR2 but not MyD88. Immunology. 2005;116:381-9 pubmed
    ..This induction signifies the presence of a TLR2-dependent but MyD88-independent M. tuberculosis signalling pathway, suggesting involvement of adaptor protein(s) other than MyD88 in M. tuberculosis-mediated induction of SLPI. ..
  68. Lebeis S, Bommarius B, Parkos C, Sherman M, Kalman D. TLR signaling mediated by MyD88 is required for a protective innate immune response by neutrophils to Citrobacter rodentium. J Immunol. 2007;179:566-77 pubmed
    ..Taken together, these experiments provide evidence for a protective role of innate immune signaling in infections caused by attaching and effacing pathogens...
  69. Medina E, Morris I, Berton M. Phosphatidylinositol 3-kinase activation attenuates the TLR2-mediated macrophage proinflammatory cytokine response to Francisella tularensis live vaccine strain. J Immunol. 2010;185:7562-72 pubmed publisher
    ..This TLR2-independent inhibitory pathway may be an important mechanism by which Francisella suppresses the host's innate immune response...
  70. Martinon F, Chen X, Lee A, Glimcher L. TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat Immunol. 2010;11:411-8 pubmed publisher
    ..Our findings identify an unsuspected critical function for XBP1 in mammalian host defenses. ..
  71. Deng Z, Poliakov A, Hardy R, Clements R, Liu C, Liu Y, et al. Adipose tissue exosome-like vesicles mediate activation of macrophage-induced insulin resistance. Diabetes. 2009;58:2498-505 pubmed publisher
    ..ELVs released by adipose tissue can act as a mode of communication between adipose tissues and macrophages. The obELV-mediated induction of TNF-alpha and IL-6 in macrophages and insulin resistance requires the TLR4/TRIF pathway. ..
  72. Bonham K, Orzalli M, Hayashi K, Wolf A, Glanemann C, Weninger W, et al. A promiscuous lipid-binding protein diversifies the subcellular sites of toll-like receptor signal transduction. Cell. 2014;156:705-16 pubmed publisher
    ..Here, we report that, in response to natural activators of innate immunity, the sorting adaptor TIRAP regulates TLR signaling from the plasma membrane and endosomes...
  73. Bernard N, Finlay C, Tannahill G, Cassidy J, O Neill L, Mills K. A critical role for the TLR signaling adapter Mal in alveolar macrophage-mediated protection against Bordetella pertussis. Mucosal Immunol. 2015;8:982-92 pubmed publisher
    ..Here we examined the role of Toll-like receptor (TLR) adapter protein Mal in the control of B. pertussis infection in the lungs. We found that B...
  74. Zhou S, Halle A, Kurt Jones E, Cerny A, Porpiglia E, Rogers M, et al. Lymphocytic choriomeningitis virus (LCMV) infection of CNS glial cells results in TLR2-MyD88/Mal-dependent inflammatory responses. J Neuroimmunol. 2008;194:70-82 pubmed publisher
    ..central nervous system (CNS) glial cells are activated by Lymphocytic Choriomeningitis Virus (LCMV) in a TLR2-MyD88/Mal-dependent manner...
  75. Andreakos E, Sacre S, Smith C, Lundberg A, Kiriakidis S, Stonehouse T, et al. Distinct pathways of LPS-induced NF-kappa B activation and cytokine production in human myeloid and nonmyeloid cells defined by selective utilization of MyD88 and Mal/TIRAP. Blood. 2004;103:2229-37 pubmed
    ..are myeloid differentiation protein 88 (MyD88) and MyD88 adaptor-like/TIR domain-containing adaptor protein (Mal/TIRAP) but their role needs to be further defined...
  76. Mohammadi N, Midiri A, Mancuso G, Patanè F, Venza M, Venza I, et al. Neutrophils Directly Recognize Group B Streptococci and Contribute to Interleukin-1? Production during Infection. PLoS ONE. 2016;11:e0160249 pubmed publisher
    ..These cells directly recognize GBS by means of endosomal TLRs and cytosolic sensors, leading to activation of the caspase-1 inflammasome. ..
  77. Liu B, Yang Y, Dai J, Medzhitov R, Freudenberg M, Zhang P, et al. TLR4 up-regulation at protein or gene level is pathogenic for lupus-like autoimmune disease. J Immunol. 2006;177:6880-8 pubmed
    ..Our study has revealed that increased TLR4 signaling alone without exogenous insult can break immunological tolerance. It provides a strong experimental evidence for TLR4 dysregulation as an etiology of lupus-like renal disease. ..
  78. Sweeney T, Suliman H, Hollingsworth J, Welty Wolf K, Piantadosi C. A toll-like receptor 2 pathway regulates the Ppargc1a/b metabolic co-activators in mice with Staphylococcal aureus sepsis. PLoS ONE. 2011;6:e25249 pubmed publisher
    ..By comparing their responses to S. aureus with WT mice, we found that MyD88-deficient and MAL-deficient mice expressed hepatic Ppargc1a and Ppargc1b normally, but that neither gene was activated in TRAM-..