IRAK4 deficiency blocks formation of the MyD88-IRAK4 Myddosome in the TLR5 pathway

Stable Identifier
R-HSA-5602603
Type
Reaction [transition]
Species
Homo sapiens
Related Species
Escherichia coli
Compartment
plasma membrane
ReviewStatus
5/5
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IRAK4 deficiency blocks formation of the MyD88-IRAK4 Myddosome in the TLR5 pathway
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Patients with an autosomal recessive form of IRAK4 deficiency bear homozygous or compound heterozygous mutations in IRAK4 gene, that result in increased susceptibility to pyogenic bacterial infections in early childhood (Picard C et al. 2010; Picard C et al. 2011). Most of the mutations are nonsense or frameshift, which create premature stop codons leading to abolished IRAK4 production (Picard C et al. 2003; Ku CL et al. 2007; Yamamoto T et al. 2014). Here we describe two nonsense mutations, IRAK4 Q293* and IRAK4 E402*, that have been shown to compromise TLR5 signaling in patients-derived peripheral blood mononucleated cells (PBMC) in response to bacterial flagellin, a TLR5 agonist (Ku CL et al. 2007). In addition, this Reactome event describes a missense variant IRAK4 R12C with expression level comparable to wild type (WT) protein 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 the 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; 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
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
Participants
Input
Participates
as an event of
Normal reaction
IRAK4 binds to MyD88 bound to the activated TLR5 or 10 receptor (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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