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Gene Review

IRAK4  -  interleukin-1 receptor-associated kinase 4

Homo sapiens

Synonyms: IPD1, IRAK-4, Interleukin-1 receptor-associated kinase 4, NY-REN-64, REN64, ...
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Disease relevance of IRAK4


High impact information on IRAK4


Chemical compound and disease context of IRAK4


Biological context of IRAK4

  • IRAK4 kinase activity is redundant for interleukin-1 (IL-1) receptor-associated kinase phosphorylation and IL-1 responsiveness [10].
  • However, they do not provide compelling evidence, as even the infectious phenotype of patients with mutations in IRAK4 may result from impaired signaling via receptors other than TLRs [11].
  • Our findings suggest synergistic effects between sequence variants in IRAK4 and the TLR 6-1-10 gene cluster [1].
  • IRAK-4 as the central TIR signaling mediator in innate immunity [12].
  • RESULTS: One child carried two germline mutations in IRAK4, and had impaired cellular responses to interleukin (IL)1 receptor and toll-like receptor (TLR) stimulation [13].

Anatomical context of IRAK4

  • We studied patients with a variety of specific inherited immunodeficiencies resulting in a lack of leukocytes, or T, B, and/or NK lymphocytes, or polymorphonuclear cells, or a lack of expression of key molecules such as HLA class II, CD40L, NF-kappaB essential modulator (NEMO), and IL-1 receptor-associated kinase-4 (IRAK-4) [14].
  • RESULTS: Impaired L-selectin shedding was observed with granulocytes from all of the interleukin-1 receptor-associated kinase-4-deficient patients on activation with agonists of Toll-like receptors 1/2, 2/6, 4, 7, and 8 and with granulocytes from all of the UNC-93B-deficient patients on activation with agonists of Toll-like receptors 7 and 8 [15].
  • SUMMARY: Antibody- and complement-mediated opsonization, splenic macrophages and interleukin-1 receptor associated kinase-4- and nuclear factor kappaB-mediated immune responses are crucial for protective immunity to S. pneumoniae [16].

Associations of IRAK4 with chemical compounds


Regulatory relationships of IRAK4

  • We present a hypothetical model of adaptation based on a signalsome, with IRAK1 evolving after IRAK4 to regulate TLR4 adaptation tightly [19].
  • By directly binding IL-1R-associated kinase (IRAK)-1 and IRAK-4, MyD88 serves as a bridging protein, enabling IRAK-4-induced IRAK-1 phosphorylation [20].

Other interactions of IRAK4

  • We have previously shown that double-stranded RNA-triggered, Toll-like receptor 3 (TLR3)-mediated signaling is independent of MyD88, IRAK4, and IRAK [21].
  • In contrast to the interleukin-1 receptor/toll-like receptor-mediated NF-kappaB pathways, the CTAR2-mediated NF-kappaB pathway does not require MyD88, IRAK1, or IRAK4 for TRAF6 engagement [22].
  • Dominant-negative forms of MyD88 and FADD, but not IRAK-4, reduced the cytocidal activity of the lipoproteins [23].
  • Cutting edge: expression of IL-1 receptor-associated kinase-4 (IRAK-4) proteins with mutations identified in a patient with recurrent bacterial infections alters normal IRAK-4 interaction with components of the IL-1 receptor complex [24].
  • IL-1 induced a strong interaction among the IL-1R, activated IRAK-1, MyD88, and WT, but not mutant, IRAK-4 [24].

Analytical, diagnostic and therapeutic context of IRAK4


  1. Interactions of sequence variants in interleukin-1 receptor-associated kinase4 and the toll-like receptor 6-1-10 gene cluster increase prostate cancer risk. Sun, J., Wiklund, F., Hsu, F.C., Bälter, K., Zheng, S.L., Johansson, J.E., Chang, B., Liu, W., Li, T., Turner, A.R., Li, L., Li, G., Adami, H.O., Isaacs, W.B., Xu, J., Grönberg, H. Cancer Epidemiol. Biomarkers Prev. (2006) [Pubmed]
  2. Heritable defects of the human TLR signalling pathways. Puel, A., Yang, K., Ku, C.L., von Bernuth, H., Bustamante, J., Santos, O.F., Lawrence, T., Chang, H.H., Al-Mousa, H., Picard, C., Casanova, J.L. J. Endotoxin Res. (2005) [Pubmed]
  3. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Picard, C., Puel, A., Bonnet, M., Ku, C.L., Bustamante, J., Yang, K., Soudais, C., Dupuis, S., Feinberg, J., Fieschi, C., Elbim, C., Hitchcock, R., Lammas, D., Davies, G., Al-Ghonaium, A., Al-Rayes, H., Al-Jumaah, S., Al-Hajjar, S., Al-Mohsen, I.Z., Frayha, H.H., Rucker, R., Hawn, T.R., Aderem, A., Tufenkeji, H., Haraguchi, S., Day, N.K., Good, R.A., Gougerot-Pocidalo, M.A., Ozinsky, A., Casanova, J.L. Science (2003) [Pubmed]
  4. IRAK-4: A New Drug Target in Inflammation, Sepsis, and Autoimmunity. Wietek, C., ONeill, L.A. Molecular interventions. (2002) [Pubmed]
  5. Two siblings with lethal pneumococcal meningitis in a family with a mutation in Interleukin-1 receptor-associated kinase 4. Enders, A., Pannicke, U., Berner, R., Henneke, P., Radlinger, K., Schwarz, K., Ehl, S. J. Pediatr. (2004) [Pubmed]
  6. Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Suzuki, N., Suzuki, S., Duncan, G.S., Millar, D.G., Wada, T., Mirtsos, C., Takada, H., Wakeham, A., Itie, A., Li, S., Penninger, J.M., Wesche, H., Ohashi, P.S., Mak, T.W., Yeh, W.C. Nature (2002) [Pubmed]
  7. Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/beta and -lambda Is IRAK-4 dependent and redundant for protective immunity to viruses. Yang, K., Puel, A., Zhang, S., Eidenschenk, C., Ku, C.L., Casrouge, A., Picard, C., von Bernuth, H., Senechal, B., Plancoulaine, S., Al-Hajjar, S., Al-Ghonaium, A., Maródi, L., Davidson, D., Speert, D., Roifman, C., Garty, B.Z., Ozinsky, A., Barrat, F.J., Coffman, R.L., Miller, R.L., Li, X., Lebon, P., Rodriguez-Gallego, C., Chapel, H., Geissmann, F., Jouanguy, E., Casanova, J.L. Immunity (2005) [Pubmed]
  8. Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections. Medvedev, A.E., Lentschat, A., Kuhns, D.B., Blanco, J.C., Salkowski, C., Zhang, S., Arditi, M., Gallin, J.I., Vogel, S.N. J. Exp. Med. (2003) [Pubmed]
  9. Glycine blunts transplantative liver ischemia-reperfusion injury by downregulating interleukin 1 receptor associated kinase-4. Liu, Z.J., Yan, L.N., Li, S.W., You, H.B., Gong, J.P. Acta Pharmacol. Sin. (2006) [Pubmed]
  10. IRAK4 kinase activity is redundant for interleukin-1 (IL-1) receptor-associated kinase phosphorylation and IL-1 responsiveness. Qin, J., Jiang, Z., Qian, Y., Casanova, J.L., Li, X. J. Biol. Chem. (2004) [Pubmed]
  11. Inherited disorders of human Toll-like receptor signaling: immunological implications. Ku, C.L., Yang, K., Bustamante, J., Puel, A., von Bernuth, H., Santos, O.F., Lawrence, T., Chang, H.H., Al-Mousa, H., Picard, C., Casanova, J.L. Immunol. Rev. (2005) [Pubmed]
  12. IRAK-4 as the central TIR signaling mediator in innate immunity. Suzuki, N., Suzuki, S., Yeh, W.C. Trends Immunol. (2002) [Pubmed]
  13. IRAK4 and NEMO mutations in otherwise healthy children with recurrent invasive pneumococcal disease. Ku, C.L., Picard, C., Erd??s, M., Jeurissen, A., Bustamante, J., Puel, A., von Bernuth, H., Filipe-Santos, O., Chang, H.H., Lawrence, T., Raes, M., Mar??di, L., Bossuyt, X., Casanova, J.L. J. Med. Genet. (2007) [Pubmed]
  14. Bacillus Calmette Guerin triggers the IL-12/IFN-gamma axis by an IRAK-4- and NEMO-dependent, non-cognate interaction between monocytes, NK, and T lymphocytes. Feinberg, J., Fieschi, C., Doffinger, R., Feinberg, M., Leclerc, T., Boisson-Dupuis, S., Picard, C., Bustamante, J., Chapgier, A., Filipe-Santos, O., Ku, C.L., de Beaucoudrey, L., Reichenbach, J., Antoni, G., Baldé, R., Alcaïs, A., Casanova, J.L. Eur. J. Immunol. (2004) [Pubmed]
  15. A fast procedure for the detection of defects in Toll-like receptor signaling. von Bernuth, H., Ku, C.L., Rodriguez-Gallego, C., Zhang, S., Garty, B.Z., Mar??di, L., Chapel, H., Chrabieh, M., Miller, R.L., Picard, C., Puel, A., Casanova, J.L. Pediatrics (2006) [Pubmed]
  16. Primary immunodeficiencies associated with pneumococcal disease. Picard, C., Puel, A., Bustamante, J., Ku, C.L., Casanova, J.L. Current opinion in allergy and clinical immunology. (2003) [Pubmed]
  17. Crystal Structures of IRAK-4 Kinase in Complex with Inhibitors: A Serine/Threonine Kinase with Tyrosine as a Gatekeeper. Wang, Z., Liu, J., Sudom, A., Ayres, M., Li, S., Wesche, H., Powers, J.P., Walker, N.P. Structure (2006) [Pubmed]
  18. Metal ion-mediated reduction in surface entropy improves diffraction quality of crystals of the IRAK-4 death domain. Lasker, M.V., Kuruvilla, S.M., Gajjar, M.M., Kapoor, A., Nair, S.K. Journal of biomolecular techniques : JBT. (2006) [Pubmed]
  19. Distinct post-receptor alterations generate gene- and signal-selective adaptation and cross-adaptation of TLR4 and TLR2 in human leukocytes. Li, L., Jacinto, R., Yoza, B., McCall, C.E. J. Endotoxin Res. (2003) [Pubmed]
  20. MyD88S, a splice variant of MyD88, differentially modulates NF-kappaB- and AP-1-dependent gene expression. Janssens, S., Burns, K., Vercammen, E., Tschopp, J., Beyaert, R. FEBS Lett. (2003) [Pubmed]
  21. Toll-like receptor 3-mediated activation of NF-kappaB and IRF3 diverges at Toll-IL-1 receptor domain-containing adapter inducing IFN-beta. Jiang, Z., Mak, T.W., Sen, G., Li, X. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  22. The C-terminal activating region 2 of the Epstein-Barr virus-encoded latent membrane protein 1 activates NF-kappaB through TRAF6 and TAK1. Wu, L., Nakano, H., Wu, Z. J. Biol. Chem. (2006) [Pubmed]
  23. Stimulation of human Toll-like receptor (TLR) 2 and TLR6 with membrane lipoproteins of Mycoplasma fermentans induces apoptotic cell death after NF-kappa B activation. Into, T., Kiura, K., Yasuda, M., Kataoka, H., Inoue, N., Hasebe, A., Takeda, K., Akira, S., Shibata, K. Cell. Microbiol. (2004) [Pubmed]
  24. Cutting edge: expression of IL-1 receptor-associated kinase-4 (IRAK-4) proteins with mutations identified in a patient with recurrent bacterial infections alters normal IRAK-4 interaction with components of the IL-1 receptor complex. Medvedev, A.E., Thomas, K., Awomoyi, A., Kuhns, D.B., Gallin, J.I., Li, X., Vogel, S.N. J. Immunol. (2005) [Pubmed]
  25. Characterization of Pellino2, a substrate of IRAK1 and IRAK4. Strelow, A., Kollewe, C., Wesche, H. FEBS Lett. (2003) [Pubmed]
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