Inhibition of interleukin 1 receptor/Toll-like receptor signaling through the alternatively spliced, short form of MyD88 is due to its failure to recruit IRAK-4.
Toll-like receptors (TLRs) and members of the proinflammatory interleukin 1 receptor (IL-1R) family are dependent on the presence of MyD88 for efficient signal transduction. The bipartite nature of MyD88 (N-terminal death domain [DD] and COOH-terminal Toll/IL-1 receptor [TIR] domain) allows it to link the TIR domain of IL-1R/TLR with the DD of the Ser/Thr kinase termed IL-1R-associated kinase (IRAK)-1. This triggers IRAK-1 phosphorylation and in turn the activation of multiple signaling cascades such as activation of the transcription factor nuclear factor (NF)-kappaB. In contrast, expression of MyD88 short (MyD88s), an alternatively spliced form of MyD88 that lacks only the short intermediate domain separating the DD and TIR domains, leads to a shutdown of IL-1/lipopolysaccharide-induced NF-kappaB activation. Here, we provide the molecular explanation for this difference. MyD88 but not MyD88s strongly interacts with IRAK-4, a newly identified kinase essential for IL-1R/TLR signaling. In the presence of MyD88s, IRAK-1 is not phosphorylated and neither activates NF-kappaB nor is ubiquitinated. Thus, MyD88s acts as a negative regulator of IL-1R/TLR/MyD88-triggered signals, leading to a transcriptionally controlled negative regulation of innate immune responses.
Burns
Kimberly
K
Institute of Biochemistry, University of Lausanne, BIL Biomedical Research Center, CH-1066 Epalinges, Switzerland.
Janssens
Sophie
S
Brissoni
Brian
B
Olivos
Natalia
N
Beyaert
Rudi
R
Tschopp
Jürg
J
D048868:Adaptor Proteins, Signal Transducing; D017398:Alternative Splicing; D000818:Animals; D000943:Antigens, Differentiation / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D029721:Drosophila Proteins; D053592:Interleukin-1 Receptor-Associated Kinases; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D029721:Drosophila Proteins; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D051193:Toll-Like Receptors; D017853:Phosphotransferases (Alcohol Group Acceptor); D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse