Defective IRAK4 does not bind MyD88:MAL:BTK:activated TLR2/4

Stable Identifier
R-HSA-5602353
Type
Reaction [transition]
Species
Homo sapiens
Related Species
Chlamydia trachomatis, Neisseria meningitidis serogroup B
Compartment
plasma membrane
Synonyms
IRAK4 deficiency blocks formation of the MyD88-IRAK4 Myddosome in TLR2/4 pathway
ReviewStatus
5/5
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Defective IRAK4 does not bind MyD88:MAL:BTK:activated TLR2/4
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Autosomal recessive IRAK4 deficiency leads to impaired TLR responses in leukocytes and is associated with increased susceptibility to pyogenic bacterial infections in childhood (Picard C et al. 2010, 2011; Medvedev AE et al. 2003; Yamamoto T et al. 2014). Here we describe two nonsense mutations IRAK4 Q293* and IRAK4 E402* that create premature stop codons leading to abolished IRAK4 production (Picard C et al. 2003; Ku CL et al. 2007; Yamamoto T et al. 2014). This Reactome event also describes the missense IRAK4 R12C variant with protein level comparable to wild type (WT) when expressed in human embryonic kidney 293 (HEK293T) cells (Ku CL et al. 2007; Yamamoto T et al. 2014). Analytical gel filtration of recombinant WT or mutant IRAK4 and MyD88 proteins revealed that IRAK4 R12C failed to form a complex with MyD88. These results are in agreement with a nuclear magnetic resonance (NMR) titration study that showed a lower affinity of IRAK4 R12C variant towards 1H-15N-labeled MyD88 N-terminal domain (Yamamoto T et al. 2014). These IRAK4 variants (Q293*, E402* and R12C) have been shown to compromise TLR2 and TLR4 signaling in response to their agonists Pam3CSK4 (TLR1/2), Pam2CSK4 (TLR2/6) and LPS (TLR4) (Ku CL et al. 2007; Yamamoto T et al. 2014; De S et al., 2018).
Literature References
PubMed ID Title Journal Year
17893200 Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity

Abel, L, Li, X, Sanlaville, D, von Bernuth, H, Miller, R, Al-Hajjar, S, Day-Good, NK, Roifman, C, Tang, M, Hara, T, Barrat, FJ, Levy, O, Holland, SM, Ehl, S, Smart, J, Gallin, J, Bossuyt, X, Geissmann, F, Speert, D, McDonald, D, Ku, CL, Takada, H, Chrabieh, M, Rodriguez-Gallego, C, Issekutz, AC, Yang, K, Garty, BZ, Puel, A, Cunningham, CK, Al-Ghonaium, A, Chang, HH, Picard, C, Maródi, L, Zhang, SY, Vivier, E, Chapel, H, Casanova, JL

J. Exp. Med. 2007
24316379 Functional assessment of the mutational effects of human IRAK4 and MyD88 genes

Kondo, N, Shirakawa, M, Ohnishi, H, Tochio, H, Kato, Z, Tsutsumi, N, Kubota, K, Yamamoto, T

Mol. Immunol. 2014
30115681 Mechanism of dysfunction of human variants of the IRAK4 kinase and a role for its kinase activity in interleukin-1 receptor signaling

Puel, A, Hoarau, C, Lin, LL, Ghandil, P, De, S, Kiessu, E, Cushing, L, Karim, F, Casanova, JL, Rao, VR

J Biol Chem 2018
12637671 Pyogenic bacterial infections in humans with IRAK-4 deficiency

Ozinsky, A, Dupuis, S, Tufenkeji, H, Al-Rayes, H, Al-Hajjar, S, Lammas, D, Frayha, HH, Day, NK, Hitchcock, R, Bustamante, J, Gougerot-Pocidalo, MA, Elbim, C, Feinberg, J, Aderem, A, Hawn, TR, Al-Mohsen, IZ, Al-Jumaah, S, Ku, CL, Yang, K, Bonnet, M, Puel, A, Al-Ghonaium, A, Picard, C, Davies, G, Haraguchi, S, Rucker, R, Good, RA, Soudais, C, Casanova, JL, Fieschi, C

Science 2003
17878374 TLR9 activation induces normal neutrophil responses in a child with IRAK-4 deficiency: involvement of the direct PI3K pathway

Lebranchu, Y, François, S, Hoarau, C, Gougerot-Pocidalo, MA, El Benna, J, Dang, PM, Lescanne, E, Grandchamp, B, Gérard, B, Elbim, C, Lacapère, JJ, Henry, D

J. Immunol. 2007
Participants
Input
Participates
as an event of
Normal reaction
IRAK4 binds to the activated TLR receptor:TIRAP:MyD88 complex (Homo sapiens)
Functional status

Loss of function of IRAK4 variants [cytosol]

Normal Entity
Disease Entity
Status
Disease
Name Identifier Synonyms
primary immunodeficiency disease DOID:612 immune deficiency disorder, immunodeficiency syndrome, hypoimmunity
Authored
Shamovsky, V  (2014-05-21)
Reviewed
D'Eustachio, P  (2014-09-06)
McDonald, DR  (2015-02-15)
Created
Shamovsky, V  (2014-06-24)
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