PMID:12872135

Citation	Hoebe, K, Du, X, Georgel, P, Janssen, E, Tabeta, K, Kim, SO, Goode, J, Lin, P, Mann, N, Mudd, S, Crozat, K, Sovath, S, Han, J and Beutler, B (2003) Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424:743-8
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.
Links	PubMed Online version:10.1038/nature01889
Keywords	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
edit table

Annotations

Gene product	Qualifier	GO ID	GO term name	Evidence Code	with/from	Aspect	Notes	Status
edit table

References

See Help:References for how to manage references in GONUTS.