Defective MyD88 does not oligomerize within the activated TLR2/4 complex

Stable Identifier
Reaction [transition]
Homo sapiens
Related Species
Chlamydia trachomatis, Neisseria meningitidis serogroup B
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All TLRs, except for TLR3, employ the MyD88-dependent signaling pathway. Autosomal recessive MyD88 deficiency predispose affected patients to recurrent pyogenic bacterial infection due to abolished TLR-mediated cytokine responses of the blood cells (von Bernuth H et al. 2008; Currie AJ et al. 2004). Here we describe several natural loss-of-function MyD88 variants (E52del, L93P, E65del, S34T) that showed severely reduced NFkB activation in human cell-based assays due to reduced homooligomerization and IRAK4 interaction, the two crucial events in the assembly of the Myddosome complex (George J et al. 2011; Nagpal K et al. 2011; Yamamoto T et al. 2014).
Literature References
PubMed ID Title Journal Year
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
20966070 Two human MYD88 variants, S34Y and R98C, interfere with MyD88-IRAK4-myddosome assembly

Wang, H, Hill, AV, Mills, TC, Motshwene, PG, Rautanen, A, Gay, NJ, Weber, AN, George, J, Kubarenko, AV

J. Biol. Chem. 2011
18669862 Pyogenic bacterial infections in humans with MyD88 deficiency

Abel, L, Li, X, von Bernuth, H, Jin, Z, Camcioglu, Y, Pascal, M, Sirvent, N, Alsina, L, Guedes, M, Antón, J, Fortuny, C, Ruiz-Ortiz, E, Herrero-Mata, MJ, Vasconcelos, J, Banchereau, J, Mustapha, IB, Yagüe, J, Aróstegui, JI, Janniere, L, Rodrigo, C, Chaussabel, D, Pankla, R, Issekutz, A, Ku, CL, Chrabieh, M, Rodriguez-Gallego, C, Garty, BZ, Puel, A, Chang, HH, Picard, C, Xiao, H, Maródi, L, Juan, M, Ghandil, P, Chapel, H, Vitor, AB, Casanova, JL, Rose, Y

Science 2008
Normal reaction
Functional status

Loss of function of MyD88 variants [cytosol]


Loss of function of MyD88 variant:TIRAP:BTK:activated TLR2/4 [plasma membrane]

Name Identifier Synonyms
primary immunodeficiency disease DOID:612 immune deficiency disorder, immunodeficiency syndrome, hypoimmunity
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