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

J Exp Med. 2003 Jan 20;197(2):263-8. doi: 10.1084/jem.20021790.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Alternative Splicing
  • Animals
  • Antigens, Differentiation / chemistry
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / metabolism*
  • Cells, Cultured
  • Drosophila Proteins*
  • Interleukin-1 Receptor-Associated Kinases
  • Membrane Glycoproteins / chemistry
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Models, Biological
  • Myeloid Differentiation Factor 88
  • NF-kappa B / metabolism
  • Phosphorylation
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Protein Structure, Tertiary
  • Receptors, Cell Surface / chemistry
  • Receptors, Cell Surface / metabolism*
  • Receptors, Immunologic / chemistry
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Receptors, Interleukin-1 / chemistry
  • Receptors, Interleukin-1 / metabolism*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • Toll-Like Receptors

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, Differentiation
  • Drosophila Proteins
  • Membrane Glycoproteins
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • Receptors, Interleukin-1
  • Recombinant Proteins
  • Toll-Like Receptors
  • Phosphotransferases (Alcohol Group Acceptor)
  • Interleukin-1 Receptor-Associated Kinases
  • Irak4 protein, mouse