Identification of Lps2 as a Key Transducer of MyD88-independent TIR Signalling

Nature. 2003 Aug 14;424(6950):743-8. doi: 10.1038/nature01889. Epub 2003 Jul 20.

Abstract

In humans, ten Toll-like receptor (TLR) paralogues sense molecular components of microbes, initiating the production of cytokine mediators that create the inflammatory response. Using N-ethyl-N-nitrosourea, we induced a germline mutation called Lps2, which abolishes cytokine responses to double-stranded RNA and severely impairs responses to the endotoxin lipopolysaccharide (LPS), indicating that TLR3 and TLR4 might share a specific, proximal transducer. Here we identify the Lps2 mutation: a distal frameshift error in a Toll/interleukin-1 receptor/resistance (TIR) adaptor protein known as Trif or Ticam-1. Trif(Lps2) homozygotes are markedly resistant to the toxic effects of LPS, and are hypersusceptible to mouse cytomegalovirus, failing to produce type I interferons when infected. Compound homozygosity for mutations at Trif and MyD88 (a cytoplasmic TIR-domain-containing adaptor protein) loci ablates all responses to LPS, indicating that only two signalling pathways emanate from the LPS receptor. However, a Trif-independent cell population is detectable when Trif(Lps2) mutant macrophages are stimulated with LPS. This reveals that an alternative MyD88-dependent 'adaptor X' pathway is present in some, but not all, macrophages, and implies afferent immune specialization.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport / genetics
  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Animals
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / physiology*
  • Escherichia coli / physiology
  • Homozygote
  • Interferon Type I / metabolism
  • Lipopolysaccharides / pharmacology*
  • Macrophages, Peritoneal / drug effects
  • Macrophages, Peritoneal / immunology
  • Macrophages, Peritoneal / microbiology
  • Macrophages, Peritoneal / virology
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Myeloid Differentiation Factor 88
  • Phenotype
  • Physical Chromosome Mapping
  • Receptors, Cell Surface / metabolism
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / physiology*
  • Sequence Analysis, DNA
  • Signal Transduction / drug effects*
  • Substrate Specificity
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha / metabolism
  • Vaccinia virus / physiology

Substances

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Antigens, Differentiation
  • Interferon Type I
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • TICAM-1 protein, mouse
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha